Abstract
Background: National investigations on the interaction of insulin resistance, β-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and β-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes. Methods: In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011–12 (baseline) and invited participants to attend follow-up visits in 2014–16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and β-cell dysfunction (HOMA of β-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. Findings: 94 952 participants (31 517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6·70, 95% CI 6·08–7·39; per unit increase in Z score: HR 2·17, 95% CI 2·10–2·24) than low HOMA-B (quartile 1 vs 4: 4·08, 3·72–4·48; per unit decrease in Z score: 1·92, 1·85–2·00). Approximately 24·4% (95% CI 23·6–25·2) of the incident diabetes could be attributed to insulin resistance and 12·4% (11·2–13·7) could be attributed to β-cell dysfunction. The HRs for diabetes were 1·83 (95% CI 1·72–1·95) per unit increase in Z score of HOMA-IR and 2·03 (1·86–2·21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·02 (1·93–2·11) and 1·88 (1·79–1·98) among participants with obesity (pinteraction=0·0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes. Interpretation: Insulin resistance shows a stronger association with incident diabetes than does β-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and β-cell dysfunction, these findings should be interpreted with caution. Funding: National Natural Science Foundation of China.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 115-124 |
| Number of pages | 10 |
| Journal | The Lancet Diabetes and Endocrinology |
| Volume | 8 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2020 |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
- Endocrinology
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Association of insulin resistance and β-cell dysfunction with incident diabetes among adults in China : a nationwide, population-based, prospective cohort study. / China Cardiometabolic Disease and Cancer Cohort Study Group.
In: The Lancet Diabetes and Endocrinology, Vol. 8, No. 2, 02.2020, p. 115-124.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Association of insulin resistance and β-cell dysfunction with incident diabetes among adults in China
T2 - a nationwide, population-based, prospective cohort study
AU - China Cardiometabolic Disease and Cancer Cohort Study Group
AU - Wang, Tiange
AU - Lu, Jieli
AU - Shi, Lixin
AU - Chen, Gang
AU - Xu, Min
AU - Xu, Yu
AU - Su, Qing
AU - Mu, Yiming
AU - Chen, Lulu
AU - Hu, Ruying
AU - Tang, Xulei
AU - Yu, Xuefeng
AU - Li, Mian
AU - Zhao, Zhiyun
AU - Chen, Yuhong
AU - Yan, Li
AU - Qin, Guijun
AU - Wan, Qin
AU - Dai, Meng
AU - Zhang, Di
AU - Gao, Zhengnan
AU - Wang, Guixia
AU - Shen, Feixia
AU - Luo, Zuojie
AU - Qin, Yingfen
AU - Chen, Li
AU - Huo, Yanan
AU - Li, Qiang
AU - Ye, Zhen
AU - Zhang, Yinfei
AU - Liu, Chao
AU - Wang, Youmin
AU - Wu, Shengli
AU - Yang, Tao
AU - Deng, Huacong
AU - Zhao, Jiajun
AU - Lai, Shenghan
AU - Bi, Yufang
AU - DeFronzo, Ralph A.
AU - Wang, Weiqing
AU - Ning, Guang
N1 - Funding Information: To the best of our knowledge, this is the first and largest nationwide prospective cohort study to examine the interactions between insulin resistance, β-cell dysfunction, and obesity and their impact on the risk of diabetes among the adult population in China. In this study, insulin resistance and β-cell dysfunction, estimated using HOMA models, were synergistically associated with a high hazard of diabetes, and insulin resistance showed a stronger association than did β-cell dysfunction with incident diabetes. These findings were consistent with those derived for adults with normal glucose tolerance or prediabetes. The stronger association of insulin resistance than of β-cell dysfunction with incident diabetes was more pronounced among adults with obesity than among adults with normal weight, indicating that obesity might modify the association between insulin resistance and diabetes in the adult population in China. Previous multi-ethnic studies have suggested differences in the pathophysiological abnormalities responsible for the development of diabetes between East Asians and white people. 5–9 It has been well accepted that the dominant aetiological factor responsible for diabetes among East Asians is β-cell dysfunction, whereas among white people insulin resistance has a more dominant role. The main determinant of such ethnic difference is that obesity is less prevalent among East Asians than among their white counterparts. 5–7 However, these conclusions were drawn from the studies based on relatively small sample sizes of Japanese and Asian-American populations. 5–9 Capturing the epidemic of both obesity and diabetes, this study provided a rare opportunity to re-examine the cause of diabetes by providing novel evidence that insulin resistance, more so than β-cell dysfunction, was a quantitatively greater risk factor for the development of diabetes in Chinese adults. This pathophysiological pattern was consistent among adults with different glucose tolerance status at baseline. Notably, we discovered significant interactions between insulin resistance and β-cell dysfunction in relation to diabetes—namely, the positive association between insulin resistance and diabetes seemed to be amplified among adults with more vulnerable β-cell function. In the most general sense, type 2 diabetes develops when there is an imbalance between the severity of insulin resistance and the compensatory increase in insulin secretion. 3,4 Thus, in the Chinese population, in which β-cell dysfunction is a common metabolic disturbance, 5–9 the development of insulin resistance cannot be offset by an increase in insulin secretion and is responsible for the elevated risk of diabetes in this ethnic population. Importantly, we found that the stronger association of insulin resistance than of β-cell dysfunction with incident diabetes was more pronounced among adults with obesity than among adults with normal weight. These findings were based on a relatively stringent definition of overweight and obesity, using BMI cutoffs of 23 kg/m 2 or more and 25 kg/m 2 or more, 20–22 respectively, and were robustly replicated in sensitivity analyses. Over the past four decades, the prevalence of diabetes in China has increased substantially and steadily in parallel with the obesity pandemic fuelled by the nutritional transition and increasingly inactive lifestyles. 10,11,17,27 Obesity is a major insulin resistance state, 12 and our findings suggest that obesity is an important determinant responsible for the stronger association of insulin resistance with diabetes in Chinese adults. The discrepancy between our findings in the Chinese population and the previous evidence derived from the Japanese population could also be partly explained by the trends in obesity prevalence over the past four decades in the two populations. 10 In China, the age-standardised percentage accounting for global obesity increased from 2·1% for men and 2·5% for women in 1975, to 16·3% for men and 12·4% for women in 2014, both ranking first in 2014 globally; at the other extreme, the age-standardised percentage of global obesity remained the lowest (<1%) in Japan over these four decades. 10 Moreover, it is important to note that in East Asians, it does not take much weight gain to cause insulin resistance and increased risk of diabetes. 5–7 In this study, we also found that even in adults with a BMI of 23–24 kg/m 2 versus less than 23 kg/m 2 , the modifying effect of a higher BMI on insulin resistance and diabetes are readily evident. These findings were further confirmed by sensitivity analysis using waist circumference, which represents a surrogate measure of visceral fat. 26 The findings of this study have important implications for diabetes prevention and control in China and even other East Asian countries. China has become the epicentre of the global diabetes crisis. 1,2 Overall, even though China makes up a fifth of the global population, about a third of adults with diabetes worldwide are Chinese. 2 Furthermore, according to data from a national survey in 2013, 35·7% of Chinese adults had prediabetes and are at increased risk of developing diabetes in the future. 27 Compared with white people (eg, the US population), the Chinese population is more likely to have a fragile β-cell function (similar to the Japanese population); 5–9 besides, the development of insulin resistance, which mainly accompanies the obesity epidemic, 10,11 could impose an extra load on β-cell function and consequently cause a more serious diabetes epidemic in the Chinese population. Our findings might provide better understanding of the pathophysiology of the diabetes in China and other East Asian countries with similar conditions and highlight the importance of treating both pathophysiological disturbances—ie, obesity-related insulin resistance and β-cell dysfunction—to retard the epidemic. Our study also emphasises the importance of obesity prevention and lifestyle modification for optimal management of diabetes. The strengths of this study include its large nationwide sample size, prospective study design, comprehensive measurements of glucose and insulin biomarkers, and thorough ascertainment of incident diabetes. The present study also has several limitations. First, we applied HOMA models as surrogates of insulin resistance and β-cell dysfunction. HOMA-IR is correlated strongly with insulin resistance indices measured by the euglycaemic-hyperinsulinaemic clamp and the minimal model analysis of intravenous glucose tolerance test, 28,29 whereas HOMA-B correlates modestly with insulin secretion indices derived from the hyperglycaemic clamp and the ratio of increment in insulin concentration to increment in glucose concentration over the first 30 min of an OGTT, 30,31 and such modest correlation could lead to an underestimated association between HOMA-B and diabetes. Although HOMA-IR and HOMA-B are the most widely accepted surrogate measures of insulin resistance and β-cell dysfunction in clinical and epidemiological studies, 32 the interpretation and extrapolation of the current epidemiological findings in the application of clinical practice should be cautious, and sophisticated gold standard methods using dynamic testing are necessary to validate these findings. Second, the large sample size of this study can enhance the reliability of our findings and has advantages in improving precision of estimates, permitting stratified analyses, and enabling detection of specific association patterns; conversely, because of the large sample size in this study, a statistically significant finding might not necessarily be clinically significant; thus, significant findings derived from this study must be analysed and interpreted with caution. Third, we have carefully adjusted for multiple confounders including socioeconomic, family history, lifestyle, and dietary factors, but bias from residual and unmeasured confounding and reverse causation is likely to be present. Fourth, the findings of this study are based on a relatively short follow-up duration. Although we have documented sufficient cases of incident diabetes (6·8%) during the follow-up period, a longer follow-up period could provide important long-term information about the interactions between insulin resistance, β-cell dysfunction, and obesity on diabetes risk. This nationwide prospective study showed that insulin resistance rather than β-cell dysfunction was more strongly associated with the risk of diabetes in the adult population in China, and this association pattern was more prominent among adults with obesity. In addition, the association between insulin resistance and diabetes seemed to be amplified among adults with worse β-cell function, indicating that insulin resistance, when added to β-cell dysfunction, might be responsible for the current diabetes epidemic in the Chinese population. The findings of this study underline the importance for managing both the pathophysiological disturbances and tackling the obesity epidemic to retard or even reverse the rapidly growing burden of diabetes in China. Contributors TW, RAD, WW, and GN were involved in the conception and design of the study. TW was responsible for drafting of the manuscript. TW, JL, and SL did the statistical analysis. TW, YB, WW, and GN obtained funding. RAD, WW, and GN supervised the study. WW and GN had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were responsible for acquisition or interpretation of data, critical revision of the manuscript for important intellectual content, and final approval of the version to be published. Declaration of interests RAD has been a member of the advisory boards for AstraZeneca, Novo Nordisk, Janssen, Boehringer-Ingelheim, Intarcia, and Elcelyx; a speaker for Novo Nordisk and AstraZeneca; and an investigator for Boehringer-Ingelheim, AstraZeneca, Janssen, and Merck. All other authors declare no competing interests. Acknowledgments This work was funded by Shanghai Key Laboratory for Endocrine Tumors, National Key R&D Program of China ( 2016YFC1305600 , 2016YFC1305202 , 2016YFC0901200 , 2016YFC1304904 , 2017YFC1310700 , 2018YFC1311705 , and 2018YFC1311800 ), National Natural Science Foundation of China ( 81530020 , 81561128019 , 81622011 , 81621061 , 81730023 , 81970728 , and 81970706 ), Shanghai Pujiang Program ( 18PJ1409600 ), and the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support from Shanghai Jiao Tong University School of Medicine ( 20171901 ). Funding Information: This work was funded by Shanghai Key Laboratory for Endocrine Tumors, National Key R&D Program of China (2016YFC1305600, 2016YFC1305202, 2016YFC0901200, 2016YFC1304904, 2017YFC1310700, 2018YFC1311705, and 2018YFC1311800), National Natural Science Foundation of China (81530020, 81561128019, 81622011, 81621061, 81730023, 81970728, and 81970706), Shanghai Pujiang Program (18PJ1409600), and the Shanghai Municipal Education Commission?Gaofeng Clinical Medicine Grant Support from Shanghai Jiao Tong University School of Medicine (20171901). Publisher Copyright: © 2020 Elsevier Ltd
PY - 2020/2
Y1 - 2020/2
N2 - Background: National investigations on the interaction of insulin resistance, β-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and β-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes. Methods: In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011–12 (baseline) and invited participants to attend follow-up visits in 2014–16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and β-cell dysfunction (HOMA of β-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. Findings: 94 952 participants (31 517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6·70, 95% CI 6·08–7·39; per unit increase in Z score: HR 2·17, 95% CI 2·10–2·24) than low HOMA-B (quartile 1 vs 4: 4·08, 3·72–4·48; per unit decrease in Z score: 1·92, 1·85–2·00). Approximately 24·4% (95% CI 23·6–25·2) of the incident diabetes could be attributed to insulin resistance and 12·4% (11·2–13·7) could be attributed to β-cell dysfunction. The HRs for diabetes were 1·83 (95% CI 1·72–1·95) per unit increase in Z score of HOMA-IR and 2·03 (1·86–2·21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·02 (1·93–2·11) and 1·88 (1·79–1·98) among participants with obesity (pinteraction=0·0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes. Interpretation: Insulin resistance shows a stronger association with incident diabetes than does β-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and β-cell dysfunction, these findings should be interpreted with caution. Funding: National Natural Science Foundation of China.
AB - Background: National investigations on the interaction of insulin resistance, β-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and β-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes. Methods: In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011–12 (baseline) and invited participants to attend follow-up visits in 2014–16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and β-cell dysfunction (HOMA of β-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. Findings: 94 952 participants (31 517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6·70, 95% CI 6·08–7·39; per unit increase in Z score: HR 2·17, 95% CI 2·10–2·24) than low HOMA-B (quartile 1 vs 4: 4·08, 3·72–4·48; per unit decrease in Z score: 1·92, 1·85–2·00). Approximately 24·4% (95% CI 23·6–25·2) of the incident diabetes could be attributed to insulin resistance and 12·4% (11·2–13·7) could be attributed to β-cell dysfunction. The HRs for diabetes were 1·83 (95% CI 1·72–1·95) per unit increase in Z score of HOMA-IR and 2·03 (1·86–2·21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·02 (1·93–2·11) and 1·88 (1·79–1·98) among participants with obesity (pinteraction=0·0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes. Interpretation: Insulin resistance shows a stronger association with incident diabetes than does β-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and β-cell dysfunction, these findings should be interpreted with caution. Funding: National Natural Science Foundation of China.
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U2 - 10.1016/S2213-8587(19)30425-5
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M3 - Article
C2 - 31879247
AN - SCOPUS:85077999442
VL - 8
SP - 115
EP - 124
JO - The Lancet Diabetes and Endocrinology
JF - The Lancet Diabetes and Endocrinology
SN - 2213-8587
IS - 2
ER -