Association between alcohol consumption and incidence of type 2 diabetes in middle-aged Japanese: Panasonic cohort study 12

Association between alcohol consumption and incidence of type 2 diabetes in middle-aged Japanese: Panasonic cohort study 12 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association between alcohol consumption and incidence of type 2 diabetes in middle-aged Japanese: Panasonic cohort study 12 Fuyuko Takahashi, Hiroshi Okada, Yoshitaka Hashimoto, Kazushiro Kurogi, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3887188/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Sep, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract This historical cohort study aimed to investigate the association between alcohol consumption and onset of type 2 diabetes in middle-aged Japanese individuals. Participants were aged 40 and above from Panasonic Corporation, Osaka, Japan’s medical health checkup program in 2008–2021. Alcohol consumption was calculated by converting the quantity consumed into daily ethanol consumption. We assessed the association between alcohol consumption and onset of type 2 diabetes using Cox regression analysis. Among 102,802 participants, 7,510 participants (7.3%) developed type 2 diabetes during the study period. Alcohol consumption at the level of 0 < to < 22 g/day and 22 to < 39 g/day were associated with a reduced risk of type 2 diabetes compared to complete alcohol abstainers. Individuals consuming alcohol at levels of 39 to < 66 g/day and at levels of ≥ 66 g/day had an increased risk of developing type 2 diabetes in participants with BMI < 25 kg/m 2 . All levels of alcohol consumption were protective against the onset of type 2 diabetes in participants with BMI ≥ 25 kg/m 2 . Moderate-to-heavy alcohol consumption poses a risk of type 2 diabetes for participants with BMI < 25 kg/m 2 , whereas alcohol intake has a protective effect on onset of type 2 diabetes among participants with BMI ≥ 25 kg/m 2 . Health sciences/Diseases/Metabolic disorders Health sciences/Risk factors Health sciences/Endocrinology/Endocrine system and metabolic diseases type 2 diabetes obesity alcohol consumption Figures Figure 1 Figure 2 1. Introduction Globally, the prevalence of diabetes is rapidly increasing. Individuals with type 2 diabetes have a high risk of complications, including cardiovascular diseases and sarcopenia 1 , 2 . Therefore, it is important to prevent the development of type 2 diabetes. Improvement in dietary habits, including alcohol consumption and exercise, is crucial for preventing the onset of diabetes 3 – 5 . Several meta-analyses have focused on Western populations regarding the association between alcohol consumption and development of diabetes. Alcohol consumption improves insulin sensitivity and reduces HbA1c levels 6 . Daily alcohol consumption 24 g was not related to the risk of type 2 diabetes 7 . The relative risk of type 2 diabetes was highest with a daily alcohol intake of 22 g in male and 24 g in female 8 . Daily alcohol consumption of less than 48 g 9 or 63 g 10 was associated with a lower risk of type 2 diabetes. In summary, light or moderate alcohol consumption may prevent the onset of type 2 diabetes in individuals from Western societies. However, previous studies focusing on Asian populations have reported varying results. One meta-analysis suggested that daily alcohol consumption > 57 g/day was associated with an increased risk of type 2 diabetes in Asian men 11 . Observational studies have reported the relationship between alcohol consumption and the onset of type 2 diabetes in Asian populations. Some reports have suggested that alcohol consumption is associated with an increased risk of type 2 diabetes 12 – 16 . Some studies have suggested that alcohol consumption is associated with a reduced risk of type 2 diabetes 17 – 19 . A report also suggested that alcohol consumption is not associated with the development of type 2 diabetes 20 . Other reports have suggested a U-shaped association between alcohol consumption and onset of type 2 diabetes 21 , 22 . In summary, the relationship between alcohol consumption and onset of diabetes in Asians remains controversial. The discrepancies in these reports among Asians can be attributed to a lack of consideration of blood tests, small sample sizes, and short observation periods in individual studies. Moreover, Asian population has a lower body mass index (BMI) and insulin resistance than Western population, suggesting that the relationship between alcohol consumption and the onset of diabetes might differ between these two populations. Therefore, in this study, we evaluated the association between alcohol consumption and the onset of type 2 diabetes in a large-scale, long-term cohort of Japanese individuals. 2. Results In total, 102,802 participants were enrolled (Fig. 1 ). Table 1 displays the baseline characteristics of the research participants. The average age and BMI were 47.9 ± 5.8 years and 23.2 ± 3.3 kg/m 2 . The proportions of a daily alcohol consumption were 35.1% for 0 g/day, 36.9% for 0 < to < 22 g/day, 17.7% for 22 to < 39 g/day, 8.7% for 39 to < 66 g/day, and 1.6% for ≥ 66 g/day. Table 2 displays type 2 diabetes incident cases and incidence rates by alcohol usage. The average follow-up duration was 7.3 ± 4.5 years. During the study period, 7,510 participants developed type 2 diabetes. The incidence rates of type 2 diabetes were 6.9% for a daily alcohol consumption of 0 g/day, 6.8% for 0 < to < 22 g/day, 7.8% for 22 to < 39 g/day, 9.6% for 39 to < 66 g/day, and 9.2% for ≥ 66 g/day in whole participants. The adjusted HRs for incident type 2 diabetes are shown in Table 3 . Multivariable analysis showed the HR of alcohol consumption at the level of 0 < to < 22 g/day (HR, 0.85; 95% CI, 0.81–0.90) and 22 to < 39 g/day (HR, 0.92; 95% CI, 0.86–0.99) were lower than those of 0 g/day. The HR of alcohol consumption at the level of 39 to < 66 g/day and ≥ 66 g/day were 0.99 (95% CI, 0.83–1.18) and 1.06 (95% CI, 0.90–1.25), respectively. The results of the subgroup analysis, examining the effects of BMI, FPG, and sex on the association between alcohol consumption levels and incident of type 2 diabetes, are shown in Figs. 2 , supplementary Fig. 1, and supplementary Fig. 2. There was an interaction effect (P for interaction < 0.0001) between alcohol consumption and BMI. In participants with BMI < 25 kg/m 2 , the HR of alcohol consumption level of 39 to < 66 g/day and ≥ 66 g/day were higher than those of 0 g/day. On the other hand, the HR of alcohol consumption level of 0 to < 22 g/day, 22 to < 39 g/day, 39 to < 66 g/day, and ≥ 66 g/day were lower than those of 0 g/day in individuals with BMI ≥ 25 kg/m 2 . We found no interaction effect between alcohol consumption, and FPG category (P for interaction = 0.13) and sex (P for interaction = 0.42). Table 1 Characteristics of participants at baseline N 102,802 Age (y) 47.9 (5.8) Male, n, (%) 79,464 (77.3) Body mass index (kg/m 2 ) 23.2 (3.3) Systolic blood pressure (mmHg) 120.0 (15.0) Diastolic blood pressure (mmHg) 75.5 (11.1) Aspartate aminotransferase (IU/L) 22.5 (12.0) Alanine aminotransferase (IU/L) 24.5 (18.2) Low-density lipoprotein cholesterol (mg/dL) 126.5 (31.1) High-density lipoprotein cholesterol (mg/dL) 60.5 (15.6) Triglycerides (mg/dL) 115.8 (90.7) Fasting plasma glucose (mg/dL) 93.9 (9.4) Uric acid (mg/dL) 5.8 (1.4) Smoking (none/past/current), n, (%) 52,324/15,853/34,625 (50.9/15.4/33.7) Alcohol consumption (none /0 < to < 22 /22 to < 39 /39 to < 66 /≥66 g/day), n, (%) 36,092/37,911/18,203/8,960/1,636 (35.1/36.9/17.7/8.7/1.6) Physical exercise, n, (%) 18,361 (17.9) Data are presented as mean (standard deviation, or percentage) or absolute number. Table 2 Incident cases and incident rate for type 2 diabetes according to alcohol consumption 0 g/day 0 < to < 22 g/day 22 to < 39 g/day 39 to < 66 g/day ≥ 66 g/day Total Whole n 36,092 37,911 18,203 8,960 1,636 10,2802 Incident diabetes (%) 2,490 (6.9) 2,594 (6.8) 1,414 (7.8) 861 (9.6) 151 (9.2) 7,510 (7.3) BMI < 25kg/m 2 n 26,521 27,984 13,736 6,509 1,197 75,947 Incident diabetes (%) 997 (3.8) 1,220 (4.4) 811 (5.9) 489 (7.5) 93 (7.8) 3,610 (4.8) BMI ≥ 25kg/m 2 n 9,571 9,927 4,467 2,451 439 26,855 Incident diabetes (%) 1,493 (15.6) 1,374 (13.8) 603 (13.5) 372 (15.2) 58 (13.2) 3,900 (14.5) FPG < 100mg/dL n 29,034 29,001 12,548 5,944 1,123 77,650 Incident diabetes (%) 823 (2.8) 744 (2.6) 314 (2.5) 200 (3.4) 43 (3.8) 2,124 (2.7) FPG ≥ 100mg/dL n 7,058 8,910 5,655 3,016 513 25,152 Incident diabetes (%) 1,667 (23.6) 1,850 (20.8) 1,100 (19.5) 661 (21.9) 108 (21.1) 5,386 (21.4) Male n 22,517 30,441 16,544 8,432 1,530 79,464 Incident diabetes (%) 2,053 (9.1) 2,431 (8.0) 1,379 (8.3) 851 (10.1) 147 (9.6) 6,861 (8.6) Female n 13,575 7,470 1,659 528 106 23,338 Incident diabetes (%) 437 (3.3) 163 (2.2) 35 (2.1) 10 (1.9) 4 (3.8) 649 (2.8) BMI, body mass index; FPG, fasting plasma glucose Table 3 Adjusted hazard ratios for incidence of type 2 diabetes during follow-up period in whole participants HR (95% CI) Age (per 1 years) 1.07 (1.07–1.08) Sex (ref: female) 1.64 (1.51–1.79) Body mass index (per 1kg/m 2 ) 1.20 (1.19–1.20) Smoking (past) (ref: none) 1.09 (1.02–1.17) Smoking (current) (ref: none) 1.44 (1.37–1.51) Alcohol consumption (ref: 0 g/day) 1 0 < to < 22 g/day 0.85 (0.81–0.90) 22 to < 39 g/day 0.92 (0.86–0.99) 39 to < 66 g/day 0.99 (0.83–1.18) ≥ 66 g/day 1.06 (0.90–1.25) Physical exercise (yes) (ref: no) 0.97 (0.91–1.03) 3. Discussion The major findings of this study were as follows: Alcohol consumption at the level of 0 < to < 22 g/day and 22 to < 39 g/day were associated with reduced risk of type 2 diabetes in middle-aged Japanese. In participants with BMI < 25 kg/m 2 , alcohol consumption level of 39 to < 66 g/day and ≥ 66 g/day were associated with an increased risk of type 2 diabetes. In the participants with BMI ≥ 25 kg/m 2 , alcohol consumption could reduce the risk of type 2 diabetes. No interaction effects were found between alcohol consumption, and FPG category and sex on the onset of type 2 diabetes. Although the mechanism through which alcohol consumption affects the risk of developing diabetes remains unknown, some studies have reported an association between alcohol consumption and insulin resistance. Alcohol consumption can improve insulin resistance 23 – 26 . Alcohol consumption increases insulin sensitivity by increasing the adiponectin and leptin levels 27 , 28 . Previous studies showed that high levels of adiponectin are closely associated with increased insulin sensitivity 29 – 31 . A previous study demonstrated that low fasting plasma adiponectin levels are linked with reduced insulin-stimulated skeletal muscle insulin receptor tyrosine phosphorylation, which could be a potential cause of decreased insulin sensitivity 32 . Alcohol has also anti-inflammatory properties. A previous study found that alcohol consumption had a U-shaped association with C-reactive protein levels 33 . Furthermore, moderate ethanol consumption inhibits interleukin-6 production or activity 34 . Inflammation is also associated with insulin resistance 35 . Moreover, alcohol consumption may indirectly affect adipocytes because it has long been known that acetate, the chief circulating metabolite of alcohol, has an antilipolytic effect on adipocytes 34 , 36 . The ability of alcohol consumption to acutely lower free fat acid levels 37 , 38 presumably reflects the generation of hepatic acetate. Therefore, alcohol consumption may prevent insulin resistance by suppressing adipocyte lipolysis, resulting in reduced levels of circulating free fatty acids. On the other hand, alcohol consumption was associated with a significant decrease in the insulin secretion level at the alcohol consumption level of ≥ 40 g/day 39 . Excessive alcohol consumption can lead to pancreatic fibrosis 40 and, depending on the amount, may potentially result in decreased insulin secretion due to alcohol intake. In this study, different results were obtained after stratification according to BMI. In participants with BMI < 25 kg/m 2 , moderate-to-high alcohol consumption increased the risk of type 2 diabetes. In participants with BMI ≥ 25 kg/m 2 , alcohol consumption reduced the risk of type 2 diabetes. As mentioned earlier, alcohol consumption is associated with improving insulin resistance. Therefore, it might exert a protective effect against the onset of diabetes in individuals with BMI ≥ 25 kg/m 2 , who are anticipated to have higher insulin resistance. Conversely, individuals with BMI < 25 kg/m 2 who are not anticipated to have high insulin resistance may be less likely to benefit from this effect and may even face an increased risk of developing diabetes due to decreased insulin secretion caused by alcohol consumption. Previous reports have suggested that the impact of alcohol on type 2 diabetes may vary depending on the BMI in Japanese individuals 41 – 44 . Waki. et al. 42 reported that moderate to high alcohol consumption increased the risk of type 2 diabetes in the participants with BMI ≤ 22 kg/m 2 , but not in the participants with BMI ≥ 22 kg/m 2 . Tsumura et al. 43 reported that moderate to high alcohol consumption reduced the risk of type 2 diabetes in the participants with BMI ≥ 22 kg/m 2 , but not in the participants with BMI < 22 kg/m 2 . Watanabe et al. 44 reported that alcohol consumption increased the risk of type 2 diabetes in the individuals with BMI < 22 kg/m 2 , but not in those with BMI ≥ 25 kg/m 2 . In summary, alcohol consumption might pose a risk of developing type 2 diabetes in the individuals with a BMI ≤ 22 kg/m 2 , but may not have an impact on those with ≥ 25 kg/m 2 . However, previous reports had serious limitations, including a small sample size, studies with short observation periods, no consideration of blood test data, and failure to consider the observation period in the analysis. The present study included only Japanese people and showed results different from the association between alcohol consumption and the onset of type 2 diabetes in Western populations. There were several reasons for this observation. Even among obese individuals, the BMI of Japanese people tends to be lower than that of Western people. Therefore, the impact of alcohol consumption may differ between Japanese and Western populations. Ethanol, which is the main component of alcoholic beverages, decomposes into acetaldehyde. Aldehyde dehydrogenase 2 (ALDH2) is required for acetaldehyde decomposition. The ALDH2 allele appears to be most prevalent in Japanese, Chinese-American, Taiwanese, Han Chinese, Koreans, and many Japanese people who are unable to metabolize alcohol adequately compared to other racial groups, such as Western people 45 . Differences in ethanol metabolism might be involved in the variations in the effects of alcohol consumption on the onset of diabetes. Moreover, a unique Japanese food culture has evolved, comprising Japanese cuisine and sake. In particular, ethyl-α-D-glucoside, which is present in sake, has been found to prevent product of interleukin 6 and liver injury 46 . A previous study showed that the intake of sake lees extract improved insulin resistance via the improvement of hepatic inflammation in an animal model 47 . Therefore, alcohol consumption, including sake, might have inhibited the development of type 2 diabetes in the Japanese participants with BMI ≥ 25 kg/m 2 . In previous reports, it has been suggested that hypertension and dyslipidemia are implicated in the onset of type 2 diabetes 48 . However, in the current study, hypertension and dyslipidemia were not included as covariates. This decision was made because we believe that alcohol consumption may also impact blood pressure and lipid levels, suggesting blood pressure and lipid levels could serve as intermediate factors in the onset of type 2 diabetes in our analyses. The present study had certain limitations. First, it was an observational study. Consequently, unknown confounding factors may have existed. Second, the data on dietary intake were not considered. A previous study reported that significantly more food was consumed in the alcohol condition than that in the no-alcohol condition 49 . Third, we were unable to sufficiently investigate the risk of type 2 diabetes associated with alcohol consumption exceeding 66 g/day. Fourth, this study did not consider the type of alcohol consumed, such as sake, beer, or wine. Fifth, previous report suggested that the ALDH2 was associated with glucose metabolism in non-obese non-diabetic Japanese 50 . Unfortunately, however, we have no data about the ALDH2. Finally, this study included only Japanese middle-aged employees. Therefore, it is unclear whether our results are applicable to other ethnic groups or populations. However, excessive alcohol consumption should be avoided, and when consuming alcohol, responsible intake is recommended because excess alcohol consumption may induce alcoholic steatohepatitis, pancreatitis, dementia, cerebral hemorrhage, and mental disorders. This large-scale and long-term study identified that light alcohol consumption might decrease the risk of developing type 2 diabetes in middle-aged Japanese people. Moderate-to-high alcohol consumption might increase the risk of developing type 2 diabetes in Japanese people with a BMI < 25 kg/m 2 . Alcohol consumption might prevent the development of type 2 diabetes in Japanese people with BMI ≥ 25 kg/m 2 . 4. Methods 4.1 Study design This long-term retrospective cohort study used data from 2008 to 2021 which were obtained from a retrospective database called the Panasonic cohort study. The Panasonic cohort study included data on annual medical health checkups, medical costs, medical history, and mortality conducted by Panasonic Corporation, Osaka, Japan. All workers underwent annual medical health check-ups. Early detection of chronic illnesses, including metabolic disorders, and assessment of underlying risk factors are the goals of this program, which aims to improve public health. Following a more than 10-hour fast, blood samples were taken. The baseline attributes were evaluated using a standardized and validated self-administered questionnaire. Participants were categorized as nonsmokers, past smokers, or current smokers. Regular exercisers were defined as those who worked out for at least 30 minutes, two days a week, for at least a year. The Panasonic Health Insurance Organization's local ethics committee granted consent for this study (approval number: 2021-001), and it was carried out in conformity with the Declaration of Helsinki's principles. The data was anonymized. Informed consent was obtained in the form of opt-out. 4.2 Alcohol consumption Alcohol consumption was determined using a questionnaire that included the amount consumed per day and frequency per week. The survey on the frequency of alcohol consumption in the questionnaire was conducted in the following format: "Do not drink at all," "1–3 days a week," "4–6 days a week," and "Every day." Additionally, the daily alcohol intake was conducted in the following format: "Less than 180 ml of sake," "180–360 ml of sake," "360–540 ml of sake," and "540 ml or more of sake." These formats are a common questionnaire format for alcohol consumption in health checkups in Japan, and the daily ethanol intake was calculated based on the average frequency and average amount of alcohol consumed per day, where 180 ml of sake is considered equivalent to 22 g of ethanol. The amount of ethanol was estimated for a person consuming 270 ml of sake in a day and was calculated to be 33 g. “Beer 500 ml” and “wine 180 ml” were converted to the equivalent of “sake 180 ml” and the ethanol content calculated. Alcohol consumption was categorized as 0 g/day, 0 < to < 22 g/day, 22 to < 39 g/day, 39 to < 66 g/day, and ≥ 66 g/day. 4.3 Inclusion and exclusion criteria Figure 1 displays the study flow diagram for participant registration. Employees aged 40 and above who underwent medical health checkups between 2008 and 2020 were enrolled in this study. We observed the onset of diabetes until 2021. Individuals who did not undergo a blood examination at baseline, those with missing data (BMI, self-administered questionnaires, or alcohol consumption), those who underwent a medical health checkup only at baseline, and those with diabetes at baseline, were excluded from the study. 4.4 Definition of type 2 diabetes A fasting plasma glucose (FPG) ≥ 126 mg/dL or diabetic therapy was considered as type 2 diabetes. Type 2 diabetes incidence was measured between 2009 and 2021. 4.5 Statistical analyses Potential confounding variables were computed to determine their means and frequencies. The incidence of type 2 diabetes was calculated according to alcohol consumption. Cox regression analysis with multivariable models was used to assess the relationship between alcohol consumption and the onset of type 2 diabetes. Alcohol consumption was divided into five groups based on the baseline self-administered questionnaire: 0 g/day, 0 < to < 22 g/day, 22 to 39 < g/day, 39 to < 66 g/day, and ≥ 66 g/day. Using a reference level of 0 g/day of alcohol consumption, the hazard ratios (HRs) were determined. The multivariable model was adjusted for BMI, sex, age, smoking status, and exercise habits. Subgroup analyses were performed to assess the effects of baseline BMI, FPG levels, and sex. The subgroups were defined as individuals with BMI < 25 kg/m2 and BMI ≥ 25 kg/m2, and individuals with FPG < 100 mg/dL and FPG ≥ 100 mg/dL at baseline. Because the Japan Society for the Study of Obesity defines obesity as a BMI of ≥ 25 kg/m2, incidence of type 2 diabetes was evaluated according to the categories of BMI < 25 kg/m2 and BMI ≥ 25 kg/m2. We also tested a potential interaction effect between BMI, FPG categories at baseline and sex, and alcohol consumption. The continuous variables are displayed either as absolute numbers or as mean ± SD. Differences were considered statistically significant at P < 0.05. Associations are presented as HRs with 95% confidence interval (95% CI). Statistical analyses were performed using the JMP software version 17 (SAS Institute, Cary, NC, USA). Declarations Author Contributions Fuyuko Takahashi wrote the manuscript. Yoshitaka Hashimoto, Hiroaki Murata, and Kazushiro Kurogi contributed to discussion. Masato Ito and Hiroshi Okada contributed to conception and discussion and researched the data. Michiaki Fukui and Hiroshi Okada edited and reviewed the manuscript. Conflict of Interest Statement Fukui M received grants from Astellas Pharma Inc., Oishi Kenko inc., Abbott Japan Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly, Japan, K.K., Taisho Pharma Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Sanwa Kagagu Kenkyusho CO., Ltd., Nippon Chemiphar Co., Ltd., Ono Pharma Co. Ltd., Kissei Pharma Co. Ltd., Takeda Pharma Co. Ltd., Mitsubishi Tanabe Pharma Corp., Novo Nordisk Pharma Ltd., Kyowa Kirin Co., Ltd., Sanofi K.K., Kowa Pharma Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Tejin Pharma Ltd., Yamada Bee Farm, and Johnson & Johnson K.K. Medical Co., and TERUMO CORPORATION. Takahashi F, Okada H, Hashimoto Y, Kurogi K, Murata H, and Ito M had no conflicts of interest to declare. References Shah, A. D. et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people. Lancet Diabetes Endocrinol 3, 105–113 (2015). Anagnostis, P. et al. Type 2 Diabetes Mellitus is Associated with Increased Risk of Sarcopenia: A Systematic Review and Meta-analysis. Calcif Tissue Int 107, 453–463 (2020). Kosaka, K., Noda, M. & Kuzuya, T. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract 67, 152–162 (2005). Grøntved, A. et al. Muscle-strengthening and conditioning activities and risk of type 2 diabetes: a prospective study in two cohorts of US women. PLoS Med 11, (2014). Saito, T. et al. Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels: a randomized controlled trial. Arch Intern Med 171, 1352–1360 (2011). Schrieks, I. C., Heil, A. L. J., Hendriks, H. F. J., Mukamal, K. J. & Beulens, J. W. J. The effect of alcohol consumption on insulin sensitivity and glycemic status: a systematic review and meta-analysis of intervention studies. Diabetes Care 38, 723–732 (2015). Li, X. H., Yu, F. F., Zhou, Y. H. & He, J. Association between alcohol consumption and the risk of incident type 2 diabetes: a systematic review and dose-response meta-analysis. Am J Clin Nutr 103, 818–829 (2016). Baliunas, D. O. et al. Alcohol as a risk factor for type 2 diabetes: A systematic review and meta-analysis. Diabetes Care 32, 2123–2132 (2009). Koppes, L. L. J., Dekker, J. M., Hendriks, H. F. J., Bouter, L. M. & Heine, R. J. Moderate alcohol consumption lowers the risk of type 2 diabetes: a meta-analysis of prospective observational studies. Diabetes Care 28, 719–725 (2005). Knott, C., Bell, S. & Britton, A. Alcohol Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of More Than 1.9 Million Individuals From 38 Observational Studies. Diabetes Care 38, 1804–1812 (2015). Han, M. The Dose-Response Relationship between Alcohol Consumption and the Risk of Type 2 Diabetes among Asian Men: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. J Diabetes Res 2020, (2020). Heianza, Y. et al. Role of alcohol drinking pattern in type 2 diabetes in Japanese men: the Toranomon Hospital Health Management Center Study 11 (TOPICS 11). Am J Clin Nutr 97, 561–568 (2013). Sawada, S. S., Lee, I. M., Muto, T., Matuszaki, K. & Blair, S. N. Cardiorespiratory fitness and the incidence of type 2 diabetes: prospective study of Japanese men. Diabetes Care 26, 2918–2922 (2003). Roh, W. G., Shin, H. C., Choi, J. H., Lee, Y. J. & Kim, K. Alcohol consumption and higher incidence of impaired fasting glucose or type 2 diabetes in obese Korean men. Alcohol 43, 643–648 (2009). Han, T. et al. Eighteen-year alcohol consumption trajectories and their association with risk of type 2 diabetes and its related factors: the China Health and Nutrition Survey. Diabetologia 62, (2019). Li, M. J. et al. Association of alcohol drinking with incident type 2 diabetes and pre-diabetes: The Guangzhou Biobank Cohort Study. Diabetes Metab Res Rev 38, (2022). Sato, K. K. et al. Relationship between drinking patterns and the risk of type 2 diabetes: the Kansai Healthcare Study. J Epidemiol Community Health ( 1978 ) 66, 507–511 (2012). Teratani, T. et al. Dose-response relationship between tobacco or alcohol consumption and the development of diabetes mellitus in Japanese male workers. Drug Alcohol Depend 125, 276–282 (2012). Shi, L. et al. Physical activity, smoking, and alcohol consumption in association with incidence of type 2 diabetes among middle-aged and elderly Chinese men. PLoS One 8, (2013). Kawakami, N., Takatsuka, N., Shimizu, H. & Ishibashi, H. Effects of smoking on the incidence of non-insulin-dependent diabetes mellitus. Replication and extension in a Japanese cohort of male employees. Am J Epidemiol 145, 103–109 (1997). Nakanishi, N., Suzuki, K. & Tatara, K. Alcohol consumption and risk for development of impaired fasting glucose or type 2 diabetes in middle-aged Japanese men. Diabetes Care 26, 48–54 (2003). Jee, S. H., Foong, A. W., Hur, N. W. & Samet, J. M. Smoking and risk for diabetes incidence and mortality in Korean men and women. Diabetes Care 33, 2567–2572 (2010). Flanagan, D. E. H. et al. Alcohol consumption and insulin resistance in young adults. Eur J Clin Invest 30, 297–301 (2000). Mayer, E. J., Newman, B., Quesenberry, C. P., Friedman, G. D. & Selby, J. V. Alcohol consumption and insulin concentrations. Role of insulin in associations of alcohol intake with high-density lipoprotein cholesterol and triglycerides. Circulation 88, 2190–2197 (1993). Facchini, F., Chen, Y. D. I. & Reaven, G. M. Light-to-moderate alcohol intake is associated with enhanced insulin sensitivity. Diabetes Care 17, 115–119 (1994). Kiechl, S. et al. Insulin sensitivity and regular alcohol consumption: large, prospective, cross sectional population study (Bruneck study). BMJ 313, 1040–1044 (1996). Ábel, T. & Fehér, J. [Effect of moderate alcohol consumption on insulin sensitivity]. Orv Hetil 150, 2218–2221 (2009). Paulson, Q. X., Hong, J., Holcomb, V. B. & Nunez, N. P. Effects of body weight and alcohol consumption on insulin sensitivity. Nutr J 9, (2010). Weyer, C. et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86, 1930–1935 (2001). Hotta, K. et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50, 1126–1133 (2001). Cnop, M. et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46, 459–469 (2003). Stefan, N. et al. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 51, 1884–1888 (2002). Imhof, A. et al. Effect of alcohol consumption on systemic markers of inflammation. Lancet 357, 763–767 (2001). McCarty, M. F. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. Med Hypotheses 52, 465–477 (1999). Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J Clin Invest 116, 1793–1801 (2006). LARSEN, T. S., NILSSON, N. Ö. & BLIX, A. S. Effects of volatile fatty acids and ketone bodies on lipolysis in isolated adipocytes from Norwegian reindeer (Rangifer tarandus). Acta Physiol Scand 117, 451–455 (1983). Christiansen, C., Thomsen, C., Rasmussen, O., Hansen, C. & Hermansen, K. The acute impact of ethanol on glucose, insulin, triacylglycerol,and free fatty acid responses and insulin sensitivity in type 2 diabetes. Br J Nutr 76, 669–675 (1996). Avogaro A, B. P. G. L. M. A. V. A. M. M. M. N. C. C. C. L. C. F. Alcohol intake impairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients. Evidence for a critical role of free fatty acids. Diabetes 42, 1626–34 (1993). Ueda, N. et al. Alcohol-induced impaired insulin secretion in a Japanese population: 5-year follow up in the Gifu Diabetes Study. J Diabetes Investig 11, 1207–1214 (2020). Zorniak, M., Sirtl, S., Mayerle, J. & Beyer, G. What Do We Currently Know about the Pathophysiology of Alcoholic Pancreatitis: A Brief Review. Visc Med 36, 182–190 (2020). Seike N, Noda M & Kadowaki T. Alcohol consumption and risk of type 2 diabetes mellitus in Japanese: a systematic review. Asia Pac J Clin Nutr 17, 545–551 (2008). Waki, K. et al. Alcohol consumption and other risk factors for self-reported diabetes among middle-aged Japanese: a population-based prospective study in the JPHC study cohort I. Diabet Med 22, 323–331 (2005). Tsumura, K. et al. Daily alcohol consumption and the risk of type 2 diabetes in Japanese men: the Osaka Health Survey. Diabetes Care 22, 1432–1437 (1999). Watanabe, M. et al. Alcohol consumption and the risk of diabetes by body mass index levels in a cohort of 5,636 Japanese. Diabetes Res Clin Pract 57, 191–197 (2002). Eng, M. Y., Luczak, S. E. & Wall, T. L. ALDH2, ADH1B, AND ADH1C GENOTYPES IN ASIANS: A LITERATURE REVIEW. Alcohol Res Health 30, 22–27 (2007). Izu, H., Hizume, K., Goto, K. & Hirotsune, M. Hepatoprotective effects of a concentrate and components of sake against galactosamine (GalN)-induced liver injury in mice. Biosci Biotechnol Biochem 71, 951–957 (2007). Kubo, H. et al. Sake lees extract improves hepatic lipid accumulation in high fat diet-fed mice. Lipids Health Dis 16, (2017). Saijo, Y. et al. The Risk Factors for Development of Type 2 Diabetes: Panasonic Cohort Study 4. Int J Environ Res Public Health 19, (2022). Yeomans, M. R. Alcohol, appetite and energy balance: is alcohol intake a risk factor for obesity? Physiol Behav 100, 82–89 (2010). Takeno, K. et al. ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men. J Clin Endocrinol Metab 106, 3573–3581 (2021). Additional Declarations Competing interest reported. Fukui M received grants from Astellas Pharma Inc., Oishi Kenko inc., Abbott Japan Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly, Japan, K.K., Taisho Pharma Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Sanwa Kagagu Kenkyusho CO., Ltd., Nippon Chemiphar Co., Ltd., Ono Pharma Co. Ltd., Kissei Pharma Co. Ltd., Takeda Pharma Co. Ltd., Mitsubishi Tanabe Pharma Corp., Novo Nordisk Pharma Ltd., Kyowa Kirin Co., Ltd., Sanofi K.K., Kowa Pharma Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Tejin Pharma Ltd., Yamada Bee Farm, and Johnson & Johnson K.K. Medical Co., and TERUMO CORPORATION. Takahashi F, Okada H, Hashimoto Y, Kurogi K, Murata H, and Ito M had no conflicts of interest to declare. Supplementary Files SFigure1600.tif SFigure2600.tif supplementaryFigurelegend.docx Cite Share Download PDF Status: Published Journal Publication published 02 Sep, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 03 May, 2024 Reviews received at journal 08 Apr, 2024 Reviewers agreed at journal 03 Apr, 2024 Reviews received at journal 15 Mar, 2024 Reviewers agreed at journal 13 Mar, 2024 Reviewers invited by journal 28 Jan, 2024 Editor assigned by journal 27 Jan, 2024 Editor invited by journal 27 Jan, 2024 Submission checks completed at journal 27 Jan, 2024 First submitted to journal 22 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3887188","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":269858147,"identity":"78bfc2c4-d5ed-49c3-9bcc-2c58c9b99b49","order_by":0,"name":"Fuyuko Takahashi","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Fuyuko","middleName":"","lastName":"Takahashi","suffix":""},{"id":269858148,"identity":"53e87376-1344-4070-a03a-50cc2fde3a1a","order_by":1,"name":"Hiroshi Okada","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYLCChIoEEMWMEJHAr4GxIeFMAgMPaVoY29C14AP87b3HHzyclyZnz97AbFzYxhDNwH74AYPlDtxaJM6cS2xI3JZjzMNzgDl5ZhtDbgNPmgGD5BncWgwkcgyBWioSeyQSmA/ztv3PbWDIYWCQbCOkZQ5cC9AW/jfEaGnIAWtJBmuRIGCLxJkzhjMSjqUZ85w52Gw84xxDbpvEM4MD+PzC395j8PFHTbIce3vzYemCMobcfv7kh48l8YQYEmBsAEcMGxAflmwgSgtSXDJ+JFbLKBgFo2AUjAQAAJuHSdXQdntVAAAAAElFTkSuQmCC","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Okada","suffix":""},{"id":269858149,"identity":"d1f2d9b6-a5ad-46e1-a6df-6001a2c463fe","order_by":2,"name":"Yoshitaka Hashimoto","email":"","orcid":"","institution":"Matsushita Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshitaka","middleName":"","lastName":"Hashimoto","suffix":""},{"id":269858150,"identity":"cb426688-6fe2-4954-a4fe-f066aa839633","order_by":3,"name":"Kazushiro Kurogi","email":"","orcid":"","institution":"Panasonic Health Insurance Organization","correspondingAuthor":false,"prefix":"","firstName":"Kazushiro","middleName":"","lastName":"Kurogi","suffix":""},{"id":269858151,"identity":"f9d10d8d-b236-4298-8c0b-65e12724e2b6","order_by":4,"name":"Hiroaki Murata","email":"","orcid":"","institution":"Matsushita Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Murata","suffix":""},{"id":269858152,"identity":"c34cad56-a7fc-4c0f-968d-a67f6641c7d3","order_by":5,"name":"Masato Ito","email":"","orcid":"","institution":"Panasonic Health Insurance Organization","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Ito","suffix":""},{"id":269858153,"identity":"9808325f-c6d4-4fab-908a-649352a0e727","order_by":6,"name":"Michiaki Fukui","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Michiaki","middleName":"","lastName":"Fukui","suffix":""}],"badges":[],"createdAt":"2024-01-22 07:17:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3887188/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3887188/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-71383-6","type":"published","date":"2024-09-02T16:04:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50393201,"identity":"016d56b8-b644-4dfe-ac25-a91ca997dbac","added_by":"auto","created_at":"2024-01-30 19:48:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20809,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study for participants’ registration\u003c/p\u003e","description":"","filename":"Figure1600.png","url":"https://assets-eu.researchsquare.com/files/rs-3887188/v1/f2fdee3258acba607e6db12e.png"},{"id":50392754,"identity":"1e3434be-3e2f-49b5-bc82-9c82f3b626e8","added_by":"auto","created_at":"2024-01-30 19:40:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32722,"visible":true,"origin":"","legend":"\u003cp\u003eAdjusted hazard ratios of alcohol consumption for incidence of type 2 diabetes according to BMI category adjusted for age, sex, smoking status, and exercise habits.\u003c/p\u003e","description":"","filename":"Figure2600.png","url":"https://assets-eu.researchsquare.com/files/rs-3887188/v1/668cecc4165ef69aaacc9fd7.png"},{"id":64185642,"identity":"6caee9d3-c117-4d3f-b554-0ffdbd78724c","added_by":"auto","created_at":"2024-09-09 16:19:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":582487,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3887188/v1/d7901ece-ae89-42e0-b420-2fcde8c886bf.pdf"},{"id":50392751,"identity":"a5584652-939d-4460-8bac-7789e1090eb7","added_by":"auto","created_at":"2024-01-30 19:40:34","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":55928,"visible":true,"origin":"","legend":"","description":"","filename":"SFigure1600.tif","url":"https://assets-eu.researchsquare.com/files/rs-3887188/v1/293f5b061f4b154ed9687d17.tif"},{"id":50393202,"identity":"c3f5a6c8-7d4f-4006-a3a5-b5bc4466203d","added_by":"auto","created_at":"2024-01-30 19:48:34","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":53384,"visible":true,"origin":"","legend":"","description":"","filename":"SFigure2600.tif","url":"https://assets-eu.researchsquare.com/files/rs-3887188/v1/518b9f1bbe06e7cd60574abe.tif"},{"id":50392755,"identity":"147de225-e33e-4bf9-8606-ba7a2fec2d28","added_by":"auto","created_at":"2024-01-30 19:40:34","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":13831,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryFigurelegend.docx","url":"https://assets-eu.researchsquare.com/files/rs-3887188/v1/ef3021f418acd77368d18db6.docx"}],"financialInterests":"Competing interest reported. Fukui M received grants from Astellas Pharma Inc., Oishi Kenko inc., Abbott Japan Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly, Japan, K.K., Taisho Pharma Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Sanwa Kagagu Kenkyusho CO., Ltd., Nippon Chemiphar Co., Ltd., Ono Pharma Co. Ltd., Kissei Pharma Co. Ltd., Takeda Pharma Co. Ltd., Mitsubishi Tanabe Pharma Corp., Novo Nordisk Pharma Ltd., Kyowa Kirin Co., Ltd., Sanofi K.K., Kowa Pharma Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Tejin Pharma Ltd., Yamada Bee Farm, and Johnson \u0026 Johnson K.K. Medical Co., and TERUMO CORPORATION.\nTakahashi F, Okada H, Hashimoto Y, Kurogi K, Murata H, and Ito M had no conflicts of interest to declare.","formattedTitle":"Association between alcohol consumption and incidence of type 2 diabetes in middle-aged Japanese: Panasonic cohort study 12","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eGlobally, the prevalence of diabetes is rapidly increasing. Individuals with type 2 diabetes have a high risk of complications, including cardiovascular diseases and sarcopenia\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Therefore, it is important to prevent the development of type 2 diabetes. Improvement in dietary habits, including alcohol consumption and exercise, is crucial for preventing the onset of diabetes\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral meta-analyses have focused on Western populations regarding the association between alcohol consumption and development of diabetes. Alcohol consumption improves insulin sensitivity and reduces HbA1c levels\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Daily alcohol consumption\u0026thinsp;\u0026lt;\u0026thinsp;24 g was associated with a lower risk of type 2 diabetes, whereas daily alcohol consumption\u0026thinsp;\u0026gt;\u0026thinsp;24 g was not related to the risk of type 2 diabetes\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The relative risk of type 2 diabetes was highest with a daily alcohol intake of 22 g in male and 24 g in female \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Daily alcohol consumption of less than 48 g \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e or 63 g \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e was associated with a lower risk of type 2 diabetes. In summary, light or moderate alcohol consumption may prevent the onset of type 2 diabetes in individuals from Western societies. However, previous studies focusing on Asian populations have reported varying results. One meta-analysis suggested that daily alcohol consumption\u0026thinsp;\u0026gt;\u0026thinsp;57 g/day was associated with an increased risk of type 2 diabetes in Asian men \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Observational studies have reported the relationship between alcohol consumption and the onset of type 2 diabetes in Asian populations. Some reports have suggested that alcohol consumption is associated with an increased risk of type 2 diabetes \u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Some studies have suggested that alcohol consumption is associated with a reduced risk of type 2 diabetes\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. A report also suggested that alcohol consumption is not associated with the development of type 2 diabetes\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Other reports have suggested a U-shaped association between alcohol consumption and onset of type 2 diabetes \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In summary, the relationship between alcohol consumption and onset of diabetes in Asians remains controversial. The discrepancies in these reports among Asians can be attributed to a lack of consideration of blood tests, small sample sizes, and short observation periods in individual studies. Moreover, Asian population has a lower body mass index (BMI) and insulin resistance than Western population, suggesting that the relationship between alcohol consumption and the onset of diabetes might differ between these two populations. Therefore, in this study, we evaluated the association between alcohol consumption and the onset of type 2 diabetes in a large-scale, long-term cohort of Japanese individuals.\u003c/p\u003e"},{"header":"2. Results","content":"\u003cp\u003eIn total, 102,802 participants were enrolled (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e displays the baseline characteristics of the research participants. The average age and BMI were 47.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8 years and 23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 kg/m\u003csup\u003e2\u003c/sup\u003e. The proportions of a daily alcohol consumption were 35.1% for 0 g/day, 36.9% for 0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day, 17.7% for 22 to \u0026lt;\u0026thinsp;39 g/day, 8.7% for 39 to \u0026lt;\u0026thinsp;66 g/day, and 1.6% for \u0026ge;\u0026thinsp;66 g/day. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e displays type 2 diabetes incident cases and incidence rates by alcohol usage. The average follow-up duration was 7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 years. During the study period, 7,510 participants developed type 2 diabetes. The incidence rates of type 2 diabetes were 6.9% for a daily alcohol consumption of 0 g/day, 6.8% for 0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day, 7.8% for 22 to \u0026lt;\u0026thinsp;39 g/day, 9.6% for 39 to \u0026lt;\u0026thinsp;66 g/day, and 9.2% for \u0026ge;\u0026thinsp;66 g/day in whole participants. The adjusted HRs for incident type 2 diabetes are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Multivariable analysis showed the HR of alcohol consumption at the level of 0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day (HR, 0.85; 95% CI, 0.81\u0026ndash;0.90) and 22 to \u0026lt;\u0026thinsp;39 g/day (HR, 0.92; 95% CI, 0.86\u0026ndash;0.99) were lower than those of 0 g/day. The HR of alcohol consumption at the level of 39 to \u0026lt;\u0026thinsp;66 g/day and \u0026ge;\u0026thinsp;66 g/day were 0.99 (95% CI, 0.83\u0026ndash;1.18) and 1.06 (95% CI, 0.90\u0026ndash;1.25), respectively. The results of the subgroup analysis, examining the effects of BMI, FPG, and sex on the association between alcohol consumption levels and incident of type 2 diabetes, are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, supplementary Fig.\u0026nbsp;1, and supplementary Fig.\u0026nbsp;2. There was an interaction effect (P for interaction\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) between alcohol consumption and BMI. In participants with BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e, the HR of alcohol consumption level of 39 to \u0026lt;\u0026thinsp;66 g/day and \u0026ge;\u0026thinsp;66 g/day were higher than those of 0 g/day. On the other hand, the HR of alcohol consumption level of 0 to \u0026lt;\u0026thinsp;22 g/day, 22 to \u0026lt;\u0026thinsp;39 g/day, 39 to \u0026lt;\u0026thinsp;66 g/day, and \u0026ge;\u0026thinsp;66 g/day were lower than those of 0 g/day in individuals with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e. We found no interaction effect between alcohol consumption, and FPG category (P for interaction\u0026thinsp;=\u0026thinsp;0.13) and sex (P for interaction\u0026thinsp;=\u0026thinsp;0.42).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of participants at baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102,802\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47.9 (5.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79,464 (77.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.2 (3.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120.0 (15.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75.5 (11.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate aminotransferase (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.5 (12.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.5 (18.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-density lipoprotein cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126.5 (31.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-density lipoprotein cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.5 (15.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115.8 (90.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting plasma glucose (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93.9 (9.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUric acid (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.8 (1.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (none/past/current), n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52,324/15,853/34,625 (50.9/15.4/33.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol consumption\u003c/p\u003e \u003cp\u003e(none /0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 /22 to \u0026lt;\u0026thinsp;39 /39 to \u0026lt;\u0026thinsp;66 /\u0026ge;66 g/day), n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36,092/37,911/18,203/8,960/1,636\u003c/p\u003e \u003cp\u003e(35.1/36.9/17.7/8.7/1.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical exercise, n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18,361 (17.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are presented as mean (standard deviation, or percentage) or absolute number.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncident cases and incident rate for type 2 diabetes according to alcohol consumption\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 g/day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 to \u0026lt;\u0026thinsp;39 g/day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39 to \u0026lt;\u0026thinsp;66 g/day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;66 g/day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36,092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37,911\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18,203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8,960\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1,636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e10,2802\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident diabetes\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,490\u003c/p\u003e \u003cp\u003e(6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2,594\u003c/p\u003e \u003cp\u003e(6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1,414\u003c/p\u003e \u003cp\u003e(7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e861\u003c/p\u003e \u003cp\u003e(9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e151\u003c/p\u003e \u003cp\u003e(9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7,510\u003c/p\u003e \u003cp\u003e(7.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u0026thinsp;\u0026lt;\u0026thinsp;25kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26,521\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27,984\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13,736\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6,509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1,197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e75,947\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident diabetes\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e997\u003c/p\u003e \u003cp\u003e(3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,220\u003c/p\u003e \u003cp\u003e(4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e811\u003c/p\u003e \u003cp\u003e(5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e489\u003c/p\u003e \u003cp\u003e(7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e93\u003c/p\u003e \u003cp\u003e(7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3,610\u003c/p\u003e \u003cp\u003e(4.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u0026thinsp;\u003cb\u003e\u0026ge;\u003c/b\u003e\u0026thinsp;25kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9,571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9,927\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4,467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2,451\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e26,855\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident diabetes\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1,493\u003c/p\u003e \u003cp\u003e(15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,374\u003c/p\u003e \u003cp\u003e(13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e603\u003c/p\u003e \u003cp\u003e(13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e372\u003c/p\u003e \u003cp\u003e(15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e58\u003c/p\u003e \u003cp\u003e(13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3,900\u003c/p\u003e \u003cp\u003e(14.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFPG\u0026thinsp;\u0026lt;\u0026thinsp;100mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29,034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29,001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12,548\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5,944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1,123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e77,650\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident diabetes\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e823\u003c/p\u003e \u003cp\u003e(2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e744\u003c/p\u003e \u003cp\u003e(2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e314\u003c/p\u003e \u003cp\u003e(2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e200\u003c/p\u003e \u003cp\u003e(3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e43\u003c/p\u003e \u003cp\u003e(3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2,124\u003c/p\u003e \u003cp\u003e(2.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFPG\u0026thinsp;\u0026ge;\u0026thinsp;100mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7,058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8,910\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5,655\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3,016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e25,152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident diabetes\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1,667\u003c/p\u003e \u003cp\u003e(23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,850\u003c/p\u003e \u003cp\u003e(20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1,100\u003c/p\u003e \u003cp\u003e(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e661\u003c/p\u003e \u003cp\u003e(21.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e108\u003c/p\u003e \u003cp\u003e(21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5,386\u003c/p\u003e \u003cp\u003e(21.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22,517\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30,441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16,544\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8,432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1,530\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e79,464\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident diabetes\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,053\u003c/p\u003e \u003cp\u003e(9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2,431\u003c/p\u003e \u003cp\u003e(8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1,379\u003c/p\u003e \u003cp\u003e(8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e851\u003c/p\u003e \u003cp\u003e(10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e147\u003c/p\u003e \u003cp\u003e(9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e6,861\u003c/p\u003e \u003cp\u003e(8.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13,575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7,470\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1,659\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e23,338\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncident diabetes\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e437\u003c/p\u003e \u003cp\u003e(3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e163\u003c/p\u003e \u003cp\u003e(2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003cp\u003e(2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e(1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e(3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e649\u003c/p\u003e \u003cp\u003e(2.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eBMI, body mass index; FPG, fasting plasma glucose\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdjusted hazard ratios for incidence of type 2 diabetes during follow-up period in whole participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (per 1 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.07 (1.07\u0026ndash;1.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (ref: female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.64 (1.51\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (per 1kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.20 (1.19\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (past) (ref: none)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.09 (1.02\u0026ndash;1.17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (current) (ref: none)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.44 (1.37\u0026ndash;1.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol consumption (ref: 0 g/day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.85 (0.81\u0026ndash;0.90)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22 to \u0026lt;\u0026thinsp;39 g/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.92 (0.86\u0026ndash;0.99)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e39 to \u0026lt;\u0026thinsp;66 g/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.99 (0.83\u0026ndash;1.18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;66 g/day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06 (0.90\u0026ndash;1.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical exercise (yes) (ref: no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97 (0.91\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThe major findings of this study were as follows: Alcohol consumption at the level of 0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day and 22 to \u0026lt;\u0026thinsp;39 g/day were associated with reduced risk of type 2 diabetes in middle-aged Japanese. In participants with BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e, alcohol consumption level of 39 to \u0026lt;\u0026thinsp;66 g/day and \u0026ge;\u0026thinsp;66 g/day were associated with an increased risk of type 2 diabetes. In the participants with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e, alcohol consumption could reduce the risk of type 2 diabetes. No interaction effects were found between alcohol consumption, and FPG category and sex on the onset of type 2 diabetes.\u003c/p\u003e \u003cp\u003eAlthough the mechanism through which alcohol consumption affects the risk of developing diabetes remains unknown, some studies have reported an association between alcohol consumption and insulin resistance. Alcohol consumption can improve insulin resistance \u003csup\u003e\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Alcohol consumption increases insulin sensitivity by increasing the adiponectin and leptin levels\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Previous studies showed that high levels of adiponectin are closely associated with increased insulin sensitivity \u003csup\u003e\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. A previous study demonstrated that low fasting plasma adiponectin levels are linked with reduced insulin-stimulated skeletal muscle insulin receptor tyrosine phosphorylation, which could be a potential cause of decreased insulin sensitivity \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Alcohol has also anti-inflammatory properties. A previous study found that alcohol consumption had a U-shaped association with C-reactive protein levels\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Furthermore, moderate ethanol consumption inhibits interleukin-6 production or activity \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Inflammation is also associated with insulin resistance\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Moreover, alcohol consumption may indirectly affect adipocytes because it has long been known that acetate, the chief circulating metabolite of alcohol, has an antilipolytic effect on adipocytes\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. The ability of alcohol consumption to acutely lower free fat acid levels \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e presumably reflects the generation of hepatic acetate. Therefore, alcohol consumption may prevent insulin resistance by suppressing adipocyte lipolysis, resulting in reduced levels of circulating free fatty acids. On the other hand, alcohol consumption was associated with a significant decrease in the insulin secretion level at the alcohol consumption level of \u0026ge;\u0026thinsp;40 g/day \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Excessive alcohol consumption can lead to pancreatic fibrosis \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e and, depending on the amount, may potentially result in decreased insulin secretion due to alcohol intake.\u003c/p\u003e \u003cp\u003eIn this study, different results were obtained after stratification according to BMI. In participants with BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e, moderate-to-high alcohol consumption increased the risk of type 2 diabetes. In participants with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e, alcohol consumption reduced the risk of type 2 diabetes. As mentioned earlier, alcohol consumption is associated with improving insulin resistance. Therefore, it might exert a protective effect against the onset of diabetes in individuals with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e, who are anticipated to have higher insulin resistance. Conversely, individuals with BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e who are not anticipated to have high insulin resistance may be less likely to benefit from this effect and may even face an increased risk of developing diabetes due to decreased insulin secretion caused by alcohol consumption. Previous reports have suggested that the impact of alcohol on type 2 diabetes may vary depending on the BMI in Japanese individuals \u003csup\u003e\u003cspan additionalcitationids=\"CR42 CR43\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Waki. et al. \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e reported that moderate to high alcohol consumption increased the risk of type 2 diabetes in the participants with BMI\u0026thinsp;\u0026le;\u0026thinsp;22 kg/m\u003csup\u003e2\u003c/sup\u003e, but not in the participants with BMI\u0026thinsp;\u0026ge;\u0026thinsp;22 kg/m\u003csup\u003e2\u003c/sup\u003e. Tsumura et al. \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e reported that moderate to high alcohol consumption reduced the risk of type 2 diabetes in the participants with BMI\u0026thinsp;\u0026ge;\u0026thinsp;22 kg/m\u003csup\u003e2\u003c/sup\u003e, but not in the participants with BMI\u0026thinsp;\u0026lt;\u0026thinsp;22 kg/m\u003csup\u003e2\u003c/sup\u003e. Watanabe et al. \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e reported that alcohol consumption increased the risk of type 2 diabetes in the individuals with BMI\u0026thinsp;\u0026lt;\u0026thinsp;22 kg/m\u003csup\u003e2\u003c/sup\u003e, but not in those with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e. In summary, alcohol consumption might pose a risk of developing type 2 diabetes in the individuals with a BMI\u0026thinsp;\u0026le;\u0026thinsp;22 kg/m\u003csup\u003e2\u003c/sup\u003e, but may not have an impact on those with \u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e. However, previous reports had serious limitations, including a small sample size, studies with short observation periods, no consideration of blood test data, and failure to consider the observation period in the analysis.\u003c/p\u003e \u003cp\u003eThe present study included only Japanese people and showed results different from the association between alcohol consumption and the onset of type 2 diabetes in Western populations. There were several reasons for this observation. Even among obese individuals, the BMI of Japanese people tends to be lower than that of Western people. Therefore, the impact of alcohol consumption may differ between Japanese and Western populations. Ethanol, which is the main component of alcoholic beverages, decomposes into acetaldehyde. Aldehyde dehydrogenase 2 (ALDH2) is required for acetaldehyde decomposition. The ALDH2 allele appears to be most prevalent in Japanese, Chinese-American, Taiwanese, Han Chinese, Koreans, and many Japanese people who are unable to metabolize alcohol adequately compared to other racial groups, such as Western people \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Differences in ethanol metabolism might be involved in the variations in the effects of alcohol consumption on the onset of diabetes. Moreover, a unique Japanese food culture has evolved, comprising Japanese cuisine and sake. In particular, ethyl-α-D-glucoside, which is present in sake, has been found to prevent product of interleukin 6 and liver injury \u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. A previous study showed that the intake of sake lees extract improved insulin resistance via the improvement of hepatic inflammation in an animal model \u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Therefore, alcohol consumption, including sake, might have inhibited the development of type 2 diabetes in the Japanese participants with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn previous reports, it has been suggested that hypertension and dyslipidemia are implicated in the onset of type 2 diabetes \u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. However, in the current study, hypertension and dyslipidemia were not included as covariates. This decision was made because we believe that alcohol consumption may also impact blood pressure and lipid levels, suggesting blood pressure and lipid levels could serve as intermediate factors in the onset of type 2 diabetes in our analyses.\u003c/p\u003e \u003cp\u003eThe present study had certain limitations. First, it was an observational study. Consequently, unknown confounding factors may have existed. Second, the data on dietary intake were not considered. A previous study reported that significantly more food was consumed in the alcohol condition than that in the no-alcohol condition \u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. Third, we were unable to sufficiently investigate the risk of type 2 diabetes associated with alcohol consumption exceeding 66 g/day. Fourth, this study did not consider the type of alcohol consumed, such as sake, beer, or wine. Fifth, previous report suggested that the ALDH2 was associated with glucose metabolism in non-obese non-diabetic Japanese \u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Unfortunately, however, we have no data about the ALDH2. Finally, this study included only Japanese middle-aged employees. Therefore, it is unclear whether our results are applicable to other ethnic groups or populations. However, excessive alcohol consumption should be avoided, and when consuming alcohol, responsible intake is recommended because excess alcohol consumption may induce alcoholic steatohepatitis, pancreatitis, dementia, cerebral hemorrhage, and mental disorders.\u003c/p\u003e \u003cp\u003eThis large-scale and long-term study identified that light alcohol consumption might decrease the risk of developing type 2 diabetes in middle-aged Japanese people. Moderate-to-high alcohol consumption might increase the risk of developing type 2 diabetes in Japanese people with a BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e. Alcohol consumption might prevent the development of type 2 diabetes in Japanese people with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e"},{"header":"4. Methods","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Study design\u003c/h2\u003e \u003cp\u003eThis long-term retrospective cohort study used data from 2008 to 2021 which were obtained from a retrospective database called the Panasonic cohort study. The Panasonic cohort study included data on annual medical health checkups, medical costs, medical history, and mortality conducted by Panasonic Corporation, Osaka, Japan. All workers underwent annual medical health check-ups. Early detection of chronic illnesses, including metabolic disorders, and assessment of underlying risk factors are the goals of this program, which aims to improve public health.\u003c/p\u003e \u003cp\u003eFollowing a more than 10-hour fast, blood samples were taken. The baseline attributes were evaluated using a standardized and validated self-administered questionnaire. Participants were categorized as nonsmokers, past smokers, or current smokers. Regular exercisers were defined as those who worked out for at least 30 minutes, two days a week, for at least a year.\u003c/p\u003e \u003cp\u003e The Panasonic Health Insurance Organization's local ethics committee granted consent for this study (approval number: 2021-001), and it was carried out in conformity with the Declaration of Helsinki's principles. The data was anonymized. Informed consent was obtained in the form of opt-out.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Alcohol consumption\u003c/h2\u003e \u003cp\u003eAlcohol consumption was determined using a questionnaire that included the amount consumed per day and frequency per week. The survey on the frequency of alcohol consumption in the questionnaire was conducted in the following format: \"Do not drink at all,\" \"1\u0026ndash;3 days a week,\" \"4\u0026ndash;6 days a week,\" and \"Every day.\" Additionally, the daily alcohol intake was conducted in the following format: \"Less than 180 ml of sake,\" \"180\u0026ndash;360 ml of sake,\" \"360\u0026ndash;540 ml of sake,\" and \"540 ml or more of sake.\" These formats are a common questionnaire format for alcohol consumption in health checkups in Japan, and the daily ethanol intake was calculated based on the average frequency and average amount of alcohol consumed per day, where 180 ml of sake is considered equivalent to 22 g of ethanol. The amount of ethanol was estimated for a person consuming 270 ml of sake in a day and was calculated to be 33 g. \u0026ldquo;Beer 500 ml\u0026rdquo; and \u0026ldquo;wine 180 ml\u0026rdquo; were converted to the equivalent of \u0026ldquo;sake 180 ml\u0026rdquo; and the ethanol content calculated. Alcohol consumption was categorized as 0 g/day, 0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day, 22 to \u0026lt;\u0026thinsp;39 g/day, 39 to \u0026lt;\u0026thinsp;66 g/day, and \u0026ge;\u0026thinsp;66 g/day.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Inclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e displays the study flow diagram for participant registration. Employees aged 40 and above who underwent medical health checkups between 2008 and 2020 were enrolled in this study. We observed the onset of diabetes until 2021. Individuals who did not undergo a blood examination at baseline, those with missing data (BMI, self-administered questionnaires, or alcohol consumption), those who underwent a medical health checkup only at baseline, and those with diabetes at baseline, were excluded from the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Definition of type 2 diabetes\u003c/h2\u003e \u003cp\u003eA fasting plasma glucose (FPG)\u0026thinsp;\u0026ge;\u0026thinsp;126 mg/dL or diabetic therapy was considered as type 2 diabetes. Type 2 diabetes incidence was measured between 2009 and 2021.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Statistical analyses\u003c/h2\u003e \u003cp\u003ePotential confounding variables were computed to determine their means and frequencies. The incidence of type 2 diabetes was calculated according to alcohol consumption. Cox regression analysis with multivariable models was used to assess the relationship between alcohol consumption and the onset of type 2 diabetes. Alcohol consumption was divided into five groups based on the baseline self-administered questionnaire: 0 g/day, 0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day, 22 to 39\u0026thinsp;\u0026lt;\u0026thinsp;g/day, 39 to \u0026lt;\u0026thinsp;66 g/day, and \u0026ge;\u0026thinsp;66 g/day. Using a reference level of 0 g/day of alcohol consumption, the hazard ratios (HRs) were determined. The multivariable model was adjusted for BMI, sex, age, smoking status, and exercise habits. Subgroup analyses were performed to assess the effects of baseline BMI, FPG levels, and sex. The subgroups were defined as individuals with BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m2 and BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m2, and individuals with FPG\u0026thinsp;\u0026lt;\u0026thinsp;100 mg/dL and FPG\u0026thinsp;\u0026ge;\u0026thinsp;100 mg/dL at baseline. Because the Japan Society for the Study of Obesity defines obesity as a BMI of \u0026ge;\u0026thinsp;25 kg/m2, incidence of type 2 diabetes was evaluated according to the categories of BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m2 and BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m2. We also tested a potential interaction effect between BMI, FPG categories at baseline and sex, and alcohol consumption.\u003c/p\u003e \u003cp\u003eThe continuous variables are displayed either as absolute numbers or as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. Differences were considered statistically significant at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Associations are presented as HRs with 95% confidence interval (95% CI). Statistical analyses were performed using the JMP software version 17 (SAS Institute, Cary, NC, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFuyuko Takahashi wrote the manuscript. Yoshitaka Hashimoto, Hiroaki Murata, and Kazushiro Kurogi contributed to discussion. Masato Ito and Hiroshi Okada contributed to conception and discussion and researched the data. Michiaki Fukui and Hiroshi Okada edited and reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFukui M received grants from Astellas Pharma Inc., Oishi Kenko inc., Abbott Japan Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly, Japan, K.K., Taisho Pharma Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Sanwa Kagagu Kenkyusho CO., Ltd., Nippon Chemiphar Co., Ltd., Ono Pharma Co. Ltd., Kissei Pharma Co. Ltd., Takeda Pharma Co. Ltd., Mitsubishi Tanabe Pharma Corp., Novo Nordisk Pharma Ltd., Kyowa Kirin Co., Ltd., Sanofi K.K., Kowa Pharma Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Tejin Pharma Ltd., Yamada Bee Farm, and Johnson \u0026amp; Johnson K.K. Medical Co., and TERUMO CORPORATION. Takahashi F, Okada H, Hashimoto Y, Kurogi K, Murata H, and Ito M had no conflicts of interest to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShah, A. D. \u003cem\u003eet al.\u003c/em\u003e Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1\u0026middot;9 million people. Lancet Diabetes Endocrinol 3, 105\u0026ndash;113 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnagnostis, P. \u003cem\u003eet al.\u003c/em\u003e Type 2 Diabetes Mellitus is Associated with Increased Risk of Sarcopenia: A Systematic Review and Meta-analysis. Calcif Tissue Int 107, 453\u0026ndash;463 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKosaka, K., Noda, M. \u0026amp; Kuzuya, T. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract 67, 152\u0026ndash;162 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGr\u0026oslash;ntved, A. \u003cem\u003eet al.\u003c/em\u003e Muscle-strengthening and conditioning activities and risk of type 2 diabetes: a prospective study in two cohorts of US women. PLoS Med 11, (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito, T. \u003cem\u003eet al.\u003c/em\u003e Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels: a randomized controlled trial. Arch Intern Med 171, 1352\u0026ndash;1360 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrieks, I. C., Heil, A. L. J., Hendriks, H. F. J., Mukamal, K. J. \u0026amp; Beulens, J. W. J. The effect of alcohol consumption on insulin sensitivity and glycemic status: a systematic review and meta-analysis of intervention studies. Diabetes Care 38, 723\u0026ndash;732 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, X. H., Yu, F. F., Zhou, Y. H. \u0026amp; He, J. Association between alcohol consumption and the risk of incident type 2 diabetes: a systematic review and dose-response meta-analysis. Am J Clin Nutr 103, 818\u0026ndash;829 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaliunas, D. O. \u003cem\u003eet al.\u003c/em\u003e Alcohol as a risk factor for type 2 diabetes: A systematic review and meta-analysis. Diabetes Care 32, 2123\u0026ndash;2132 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoppes, L. L. J., Dekker, J. M., Hendriks, H. F. J., Bouter, L. M. \u0026amp; Heine, R. J. Moderate alcohol consumption lowers the risk of type 2 diabetes: a meta-analysis of prospective observational studies. Diabetes Care 28, 719\u0026ndash;725 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnott, C., Bell, S. \u0026amp; Britton, A. Alcohol Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of More Than 1.9 Million Individuals From 38 Observational Studies. Diabetes Care 38, 1804\u0026ndash;1812 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan, M. The Dose-Response Relationship between Alcohol Consumption and the Risk of Type 2 Diabetes among Asian Men: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. \u003cem\u003eJ Diabetes Res\u003c/em\u003e 2020, (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeianza, Y. \u003cem\u003eet al.\u003c/em\u003e Role of alcohol drinking pattern in type 2 diabetes in Japanese men: the Toranomon Hospital Health Management Center Study 11 (TOPICS 11). Am J Clin Nutr 97, 561\u0026ndash;568 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSawada, S. S., Lee, I. M., Muto, T., Matuszaki, K. \u0026amp; Blair, S. N. Cardiorespiratory fitness and the incidence of type 2 diabetes: prospective study of Japanese men. Diabetes Care 26, 2918\u0026ndash;2922 (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoh, W. G., Shin, H. C., Choi, J. H., Lee, Y. J. \u0026amp; Kim, K. Alcohol consumption and higher incidence of impaired fasting glucose or type 2 diabetes in obese Korean men. Alcohol 43, 643\u0026ndash;648 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan, T. \u003cem\u003eet al.\u003c/em\u003e Eighteen-year alcohol consumption trajectories and their association with risk of type 2 diabetes and its related factors: the China Health and Nutrition Survey. \u003cem\u003eDiabetologia\u003c/em\u003e 62, (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, M. J. \u003cem\u003eet al.\u003c/em\u003e Association of alcohol drinking with incident type 2 diabetes and pre-diabetes: The Guangzhou Biobank Cohort Study. Diabetes Metab Res Rev 38, (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSato, K. K. \u003cem\u003eet al.\u003c/em\u003e Relationship between drinking patterns and the risk of type 2 diabetes: the Kansai Healthcare Study. \u003cem\u003eJ Epidemiol Community Health (\u003c/em\u003e1978\u003cem\u003e)\u003c/em\u003e 66, 507\u0026ndash;511 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeratani, T. \u003cem\u003eet al.\u003c/em\u003e Dose-response relationship between tobacco or alcohol consumption and the development of diabetes mellitus in Japanese male workers. Drug Alcohol Depend 125, 276\u0026ndash;282 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi, L. \u003cem\u003eet al.\u003c/em\u003e Physical activity, smoking, and alcohol consumption in association with incidence of type 2 diabetes among middle-aged and elderly Chinese men. PLoS One 8, (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawakami, N., Takatsuka, N., Shimizu, H. \u0026amp; Ishibashi, H. Effects of smoking on the incidence of non-insulin-dependent diabetes mellitus. Replication and extension in a Japanese cohort of male employees. Am J Epidemiol 145, 103\u0026ndash;109 (1997).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakanishi, N., Suzuki, K. \u0026amp; Tatara, K. Alcohol consumption and risk for development of impaired fasting glucose or type 2 diabetes in middle-aged Japanese men. Diabetes Care 26, 48\u0026ndash;54 (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJee, S. H., Foong, A. W., Hur, N. W. \u0026amp; Samet, J. M. Smoking and risk for diabetes incidence and mortality in Korean men and women. Diabetes Care 33, 2567\u0026ndash;2572 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFlanagan, D. E. H. \u003cem\u003eet al.\u003c/em\u003e Alcohol consumption and insulin resistance in young adults. Eur J Clin Invest 30, 297\u0026ndash;301 (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMayer, E. J., Newman, B., Quesenberry, C. P., Friedman, G. D. \u0026amp; Selby, J. V. Alcohol consumption and insulin concentrations. Role of insulin in associations of alcohol intake with high-density lipoprotein cholesterol and triglycerides. Circulation 88, 2190\u0026ndash;2197 (1993).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFacchini, F., Chen, Y. D. I. \u0026amp; Reaven, G. M. Light-to-moderate alcohol intake is associated with enhanced insulin sensitivity. Diabetes Care 17, 115\u0026ndash;119 (1994).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKiechl, S. \u003cem\u003eet al.\u003c/em\u003e Insulin sensitivity and regular alcohol consumption: large, prospective, cross sectional population study (Bruneck study). BMJ 313, 1040\u0026ndash;1044 (1996).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u0026Aacute;bel, T. \u0026amp; Feh\u0026eacute;r, J. [Effect of moderate alcohol consumption on insulin sensitivity]. Orv Hetil 150, 2218\u0026ndash;2221 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaulson, Q. X., Hong, J., Holcomb, V. B. \u0026amp; Nunez, N. P. Effects of body weight and alcohol consumption on insulin sensitivity. Nutr J 9, (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeyer, C. \u003cem\u003eet al.\u003c/em\u003e Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86, 1930\u0026ndash;1935 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHotta, K. \u003cem\u003eet al.\u003c/em\u003e Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50, 1126\u0026ndash;1133 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCnop, M. \u003cem\u003eet al.\u003c/em\u003e Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46, 459\u0026ndash;469 (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStefan, N. \u003cem\u003eet al.\u003c/em\u003e Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 51, 1884\u0026ndash;1888 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImhof, A. \u003cem\u003eet al.\u003c/em\u003e Effect of alcohol consumption on systemic markers of inflammation. Lancet 357, 763\u0026ndash;767 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCarty, M. F. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. Med Hypotheses 52, 465\u0026ndash;477 (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShoelson, S. E., Lee, J. \u0026amp; Goldfine, A. B. Inflammation and insulin resistance. J Clin Invest 116, 1793\u0026ndash;1801 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLARSEN, T. S., NILSSON, N. \u0026Ouml;. \u0026amp; BLIX, A. S. Effects of volatile fatty acids and ketone bodies on lipolysis in isolated adipocytes from Norwegian reindeer (Rangifer tarandus). Acta Physiol Scand 117, 451\u0026ndash;455 (1983).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChristiansen, C., Thomsen, C., Rasmussen, O., Hansen, C. \u0026amp; Hermansen, K. The acute impact of ethanol on glucose, insulin, triacylglycerol,and free fatty acid responses and insulin sensitivity in type 2 diabetes. Br J Nutr 76, 669\u0026ndash;675 (1996).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvogaro A, B. P. G. L. M. A. V. A. M. M. M. N. C. C. C. L. C. F. Alcohol intake impairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients. Evidence for a critical role of free fatty acids. Diabetes 42, 1626\u0026ndash;34 (1993).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUeda, N. \u003cem\u003eet al.\u003c/em\u003e Alcohol-induced impaired insulin secretion in a Japanese population: 5-year follow up in the Gifu Diabetes Study. J Diabetes Investig 11, 1207\u0026ndash;1214 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZorniak, M., Sirtl, S., Mayerle, J. \u0026amp; Beyer, G. What Do We Currently Know about the Pathophysiology of Alcoholic Pancreatitis: A Brief Review. Visc Med 36, 182\u0026ndash;190 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeike N, Noda M \u0026amp; Kadowaki T. Alcohol consumption and risk of type 2 diabetes mellitus in Japanese: a systematic review. Asia Pac J Clin Nutr 17, 545\u0026ndash;551 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWaki, K. \u003cem\u003eet al.\u003c/em\u003e Alcohol consumption and other risk factors for self-reported diabetes among middle-aged Japanese: a population-based prospective study in the JPHC study cohort I. Diabet Med 22, 323\u0026ndash;331 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsumura, K. \u003cem\u003eet al.\u003c/em\u003e Daily alcohol consumption and the risk of type 2 diabetes in Japanese men: the Osaka Health Survey. Diabetes Care 22, 1432\u0026ndash;1437 (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatanabe, M. \u003cem\u003eet al.\u003c/em\u003e Alcohol consumption and the risk of diabetes by body mass index levels in a cohort of 5,636 Japanese. Diabetes Res Clin Pract 57, 191\u0026ndash;197 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEng, M. Y., Luczak, S. E. \u0026amp; Wall, T. L. ALDH2, ADH1B, AND ADH1C GENOTYPES IN ASIANS: A LITERATURE REVIEW. Alcohol Res Health 30, 22\u0026ndash;27 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIzu, H., Hizume, K., Goto, K. \u0026amp; Hirotsune, M. Hepatoprotective effects of a concentrate and components of sake against galactosamine (GalN)-induced liver injury in mice. Biosci Biotechnol Biochem 71, 951\u0026ndash;957 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKubo, H. \u003cem\u003eet al.\u003c/em\u003e Sake lees extract improves hepatic lipid accumulation in high fat diet-fed mice. Lipids Health Dis 16, (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaijo, Y. \u003cem\u003eet al.\u003c/em\u003e The Risk Factors for Development of Type 2 Diabetes: Panasonic Cohort Study 4. Int J Environ Res Public Health 19, (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeomans, M. R. Alcohol, appetite and energy balance: is alcohol intake a risk factor for obesity? Physiol Behav 100, 82\u0026ndash;89 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakeno, K. \u003cem\u003eet al.\u003c/em\u003e ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men. J Clin Endocrinol Metab 106, 3573\u0026ndash;3581 (2021).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"type 2 diabetes, obesity, alcohol consumption","lastPublishedDoi":"10.21203/rs.3.rs-3887188/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3887188/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis historical cohort study aimed to investigate the association between alcohol consumption and onset of type 2 diabetes in middle-aged Japanese individuals.\u003c/p\u003e \u003cp\u003eParticipants were aged 40 and above from Panasonic Corporation, Osaka, Japan\u0026rsquo;s medical health checkup program in 2008\u0026ndash;2021. Alcohol consumption was calculated by converting the quantity consumed into daily ethanol consumption. We assessed the association between alcohol consumption and onset of type 2 diabetes using Cox regression analysis.\u003c/p\u003e \u003cp\u003eAmong 102,802 participants, 7,510 participants (7.3%) developed type 2 diabetes during the study period. Alcohol consumption at the level of 0\u0026thinsp;\u0026lt;\u0026thinsp;to \u0026lt;\u0026thinsp;22 g/day and 22 to \u0026lt;\u0026thinsp;39 g/day were associated with a reduced risk of type 2 diabetes compared to complete alcohol abstainers. Individuals consuming alcohol at levels of 39 to \u0026lt;\u0026thinsp;66 g/day and at levels of \u0026ge;\u0026thinsp;66 g/day had an increased risk of developing type 2 diabetes in participants with BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e. All levels of alcohol consumption were protective against the onset of type 2 diabetes in participants with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eModerate-to-heavy alcohol consumption poses a risk of type 2 diabetes for participants with BMI\u0026thinsp;\u0026lt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e, whereas alcohol intake has a protective effect on onset of type 2 diabetes among participants with BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e","manuscriptTitle":"Association between alcohol consumption and incidence of type 2 diabetes in middle-aged Japanese: Panasonic cohort study 12","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-30 19:40:29","doi":"10.21203/rs.3.rs-3887188/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-03T12:03:49+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-08T23:26:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"00d49a59-5042-4e70-8ff7-5893a95249d4","date":"2024-04-03T21:25:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-15T05:35:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4e8f30e6-d78e-4851-a0c9-a6a0d3a995c5","date":"2024-03-13T20:18:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-28T07:08:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-27T12:27:39+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-01-27T06:34:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-27T06:33:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-01-22T07:06:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe6be7e2-d8b5-4990-9efe-d72f3922684f","owner":[],"postedDate":"January 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28425471,"name":"Health sciences/Diseases/Metabolic disorders"},{"id":28425472,"name":"Health sciences/Risk factors"},{"id":28425473,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases"}],"tags":[],"updatedAt":"2024-09-09T16:09:04+00:00","versionOfRecord":{"articleIdentity":"rs-3887188","link":"https://doi.org/10.1038/s41598-024-71383-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-09-02 16:04:52","publishedOnDateReadable":"September 2nd, 2024"},"versionCreatedAt":"2024-01-30 19:40:29","video":"","vorDoi":"10.1038/s41598-024-71383-6","vorDoiUrl":"https://doi.org/10.1038/s41598-024-71383-6","workflowStages":[]},"version":"v1","identity":"rs-3887188","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3887188","identity":"rs-3887188","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}