Diabetes Care Volume 43, April 2020 719

Hao Ma,1 Xiang Li,1 Tao Zhou,1

Glucosamine Use, Inflammation, CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL CLIN Dianjianyi Sun,1,2 Zhaoxia Liang,1,3 Ying Li,4 and Genetic Susceptibility, and Yoriko Heianza,1 and Lu Qi1,5,6 Incidence of Type 2 Diabetes: A Prospective Study in UK Biobank

Diabetes Care 2020;43:719–725 | https://doi.org/10.2337/dc19-1836

OBJECTIVE Glucosamine is a widely used supplement typically taken for osteoarthritis and joint pain. Emerging evidence suggests potential links of glucosamine with glucose metabolism, inflammation, and cardiometabolic risk. We prospectively analyzed the association of habitual glucosamine use with risk of type 2 diabetes (T2D) and assessed whether genetic susceptibility and inflammation status might modify the association.

RESEARCH DESIGN AND METHODS This study analyzed 404,508 participants from the UK Biobank who were free of diabetes, cancer, or cardiovascular disease at baseline and completed the ques- tionnaire on supplement use. Cox proportional hazards models were used to 1Department of Epidemiology, School of Public evaluate the association between habitual use of glucosamine and risk of incident Health and Tropical Medicine, Tulane University, New Orleans, LA T2D. 2Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health RESULTS Science Center, Beijing, China During a median of 8.1 years of follow-up, 7,228 incident cases of T2D were 3Department of Obstetrics, Women’s Hospital, documented. Glucosamine use was associated with a significantly lower risk of T2D Zhejiang University School of Medicine, Hang- – zhou, Zhejiang Province, China (hazard ratio 0.83, 95% CI 0.78 0.89) after adjustment for age, sex, BMI, race, center, 4The National Key Discipline, Department of Nu- Townsend deprivation index, lifestyle factors, history of disease, and other trition and Food Hygiene, School of Public Health, supplement use. This inverse association was more pronounced in participants Harbin Medical University, Harbin, China 5 with a higher blood level of baseline C-reactive protein than in those with a lower Channing Division of Network Medicine, De- ’ fl P 5 partment of Medicine, Brigham and Women s level of this in ammation marker ( -interaction 0.02). A genetic risk score for T2D Hospital and Harvard Medical School, Boston, did not modify this association (P-interaction 5 0.99). MA 6Department of Nutrition, Harvard T.H. Chan CONCLUSIONS School of Public Health, Boston, MA Our findings indicate that glucosamine use is associated with a lower risk of Corresponding author: Lu Qi, [email protected]; incident T2D. [email protected] Received 14 September 2019 and accepted 6 January 2020 Glucosamine is a widely used supplement typically taken for osteoarthritis and joint This article contains Supplementary Data online pain (1). It has been estimated that ;20% of middle-aged adults use this supplement at https://care.diabetesjournals.org/lookup/suppl/ in the U.S., U.K., and Australia (2–4), although studies on the effectiveness of doi:10.2337/dc19-1836/-/DC1. glucosamine on osteoarthritis have reported conflicting results (5). © 2020 by the American Diabetes Association. In a recent study, we found that habitual glucosamine use was significantly Readers may use this article as long as the work is properly cited, the use is educational and not for associated with lower risks of cardiovascular diseases (4). Notably, previous studies profit, and the work is not altered. More infor- have also linked glucosamine use with glucose metabolism, although the evidence is mation is available at https://www.diabetesjournals not consistent. Several in vitro studies reported that glucosamine altered glucose .org/content/license. 720 Glucosamine Inversely Associated With T2D Diabetes Care Volume 43, April 2020

metabolism and induced insulin resistance Exposure Assessment genetic predispositiontoT2D.Detailedin- (6–8); however, these findings have not Habitual glucosamine information was formation about genotyping, imputation, been confirmed in human studies (9–12). collected through a baseline touch-screen and quality control in the UK Biobank study In contrast, a long-term clinical trial (3 questionnaire. Participants were asked, has been described previously (25). years) of glucosamine intervention in “Do you regularly take any of the follow- 212 participants showed that a slightly ing?” Participants selected more than one Ascertainment of Outcomes glucose-lowering effect was observed in answerfromalistofsupplementsthrough The prevalent diabetes was assessed glucosamine users (13). In addition, pre- the touch-screen questionnaire. We de- based on the UK Biobank algorithms for vious studies suggest that glucosamine fined glucosamine users as follows: 0, no; 1, the diagnosis of diabetes (26) (Supplementary may affect inflammation status (14–16), yes. Two repeated surveys (the first visit Table 2). Incident T2D was ascertained which also has been related to glucose was completed from 2012 to 2013; the using hospital inpatient records contain- metabolism, insulin resistance, and risk second visit was conducted in 20141) ing data on admissions and diagnoses of type 2 diabetes (T2D) (17,18). We there- conducted in 16,687 and 30,972 partici- obtained from the Hospital Episode Sta- fore hypothesized that habitual glucos- pants, respectively, were used to assess the tistics for England, Scottish Morbidity Re- amine use may be related to T2D risk. No reproducibility and validity of glucosamine cord data for Scotland, and the Patient study has analyzed the association be- use with the same touch-screen question- Episode Database for Wales. T2D was tween habitual glucosamine use and in- naire. In the first repeated survey, 56.4% defined by the ICD-10 code E11. Informa- cident T2D in prospective cohorts. (2,183 of 3,872) of baseline glucosamine tion on timing of incident T2D was col- In this study, we prospectively inves- users reported that they continued to take lected through cumulative medical records tigated the association of habitual glu- glucosamine (Spearman r 5 0.55), and of hospital diagnoses (until 31 March 2017). cosamine use with risk of T2D in 404,508 42.0% (2,711 of 6,455) of baseline glucos- Detailed information on the ascertainment adults from the UK Biobank study. We amine users reported that they continued of T2D is available online at https://biobank particularly examined the potential ef- to take glucosamine (Spearman r50.43) in .ctsu.ox.ac.uk/showcase/label.cgi?id52000. fect modification of inflammation on the the second repeated survey (20141). associations. In addition, because previ- Blood samples were collected at base- Statistical Analysis ous studies, including ours (19,20), sug- line (2006–2010). CRP (mg/L) was mea- Cox proportional hazards models were gest that the genetic variations may sured by immunoturbidimetric assay on a used to calculate the hazard ratios (HRs) modify the associations between di- Beckman Coulter AU5800, glucose (mmol/L) comparing incident T2D rates in partic- etary/lifestyle factors and disease risk, was measured by hexokinase analysis on a ipants who did and did not use glucosamine. we also assessed the interaction between Beckman Coulter AU5800, and HbA1c (mmol/ The proportional hazards assumption was glucosamine use and genetic susceptibil- mol) was measured by high-performance tested using Schoenfeld residuals. A gen- ity on the associations. liquid chromatography analysis on a Bio- eral linear model was used to evaluate the Rad VARIANT II Turbo. Calibration and qual- association of glucosamine use with glu- RESEARCH DESIGN AND METHODS ity control were conducted according to the cose levels, CRP levels, and HbA1c levels. Study Population manufacturer’s recommendations. In addi- Several potential confounders were ad- The UK Biobank is a large population- tion, nearly half of the CRP values fell justedinthesemodels,includingage(years), based cohort study comprising .0.5 mil- between 0 and 1, and the distribution was sex,race(white,mixed,Asian,black,others), lion participants in the UK. The details of right-skewed; thus, log (units 1 1) of CRP assessment centers, BMI (,18.5, 18.5–24.9 the study design have been described values was used in all analyses (22). or 25–29.9, $30 kg/m2), Townsend dep- in previous studies (21). All participants Further details of these measurements rivation index (quintiles), smoking status provided written informed consent, and can be found at the UK Biobank website (current, past, never), physical activity the study was approved by the North (https://biobank.ctsu.ox.ac.uk/showcase). ($600 MET min/week or ,600 MET West Multi-centre Research Ethics Com- We created a genetic risk score (GRS) min/week, which was calculated accord- mittee and the Tulane University (New for T2D using 102 single nucleotide poly- ing to the International Physical Activity Orleans, LA) Biomedical Committee In- morphisms (SNPs),which passed quality Questionnaire short form) (27), moderate stitutional Review Board. In the main anal- control, based on the previous study (23) drinking (women: .0and#14 g/day, ysis of this study, we included 404,508 (Supplementary Table 1). A weighted method men: .0and#28 g/day, https://health participants who had complete data on was used to calculate the T2D-GRS. Each .gov/our-work/food-nutrition/2015-2020- the use of glucosamine and were free of SNP was recoded as 0, 1, or 2 according to dietary-guidelines/guidelines/appendix-9/), diabetes, cardiovascular disease, or can- the number of risk alleles, and each SNP healthy diet, family history of diabetes, cer at baseline. was multiplied by a weighted risk esti- hypertension, high cholesterol, osteoar- Geneticdatawereavailablefor360,550 mate (b-coefficient) on T2D obtained thritis or joint pain, aspirin use, nonaspirin white participants in this study after ex- from the previous genome-wide associ- nonsteroidalanti-inflammatorydrug (NSAID) cluding participants with sex discordance ation study. The genetic risk score was use, vitamin supplement use, and nonvita- or high missingness/heterozygosity and calculated by using the equation: GRS 5 min supplement use. Details of the as- those who had a genetic relatedness with (b1 3 SNP1 1 b2 3 SNP2 1...1 b102 3 sessment of covariates are described in others.C-reactive protein (CRP)datawere SNP102) 3 (102/sum of the b-coefficients), the Supplementary Materials. For analyses available for 381,165 participants in this where SNPnis the risk allele number of each of genetic data, we also adjusted for the first study after further excluding participants SNP (24). The T2D-GRS ranged from 73.8 to 10 genetic principal components and geno- with missing data. 133.0, with higher scores indicating a higher typing array (106 batches); for analyses that care.diabetesjournals.org Ma and Associates 721

included glucose levels, we also adjusted for RESULTS inverse association with glucose levels b 52 , fasting time. In addition, we created an overall Baseline Characteristics of Participants ( 0.01, P 0.001) or HbA1c levels healthy lifestyle score based on BMI (,30 kg/ According to Glucosamine Use (b 520.03, P 5 0.13) at baseline. 2 m ), physical activity ($600 MET min/week), Table 1reports baseline characteristics of smoking (never), and healthy diet (yes). Miss- study participants according to the use of Association Between Glucosamine Use ing data were coded as a missing indicator glucosamine. At baseline, 19.4% of the and Risk of Incident T2D categoryforcategoricalvariablesandwith study population reported glucosamine Duringa median of 8.1years of follow-up, mean values for continuous variables. use. Glucosamine users were older, more we documented 7,228 incident cases of We performed stratified analysis to likely to be women, and less likely to be T2D. Glucosamine use was significantly evaluate potential modification effects current smokers. They tended to have a associated with a lower risk of incident by the following factors: sex (women or healthy diet, were more likely to have T2D. In the age- and sex-adjusted anal- men), age (,55 or $55 years), BMI (,30 higher physical activity level, a lower yses, the HR associated with glucosamine 2 or $30 kg/m ), physical activity (,600 Townsend deprive index, higher preva- use was 0.82 (95% CI 0.77–0.87). After MET min/week or $600 MET min/week), lence of hypertension, and high choles- further adjustment for race, BMI, assess- smoking (never, past, current), healthy terol compared with nonusers. Glucosamine ment center, physical activity, smoking diet (no or yes), overall healthy lifestyle users also tended to have a history of status, moderate drinking, healthy diet, score (0–1, 2–3, and 4), Townsend dep- osteoarthritis or joint pain and took other Townsend deprivation index, family his- rivation index (,median or $median), supplements and anti-inflammatory drugs. tory of diabetes, aspirin use, nonaspirin hypertension (no or yes), high choles- After adjustment for covariates includ- NSAID use, osteoarthritis or joint pain, terol (no or yes), osteoarthritis or joint ing age, sex, race, BMI, assessment cen- hypertension, and high cholesterol, the pain (no or yes), vitamin supplement use ter, physical activity, smoking status, HR associated with glucosamine use was (no or yes), nonvitamin supplement use moderate drinking, healthy diet, Town- 0.81 (95% CI 0.76–0.86). The results did (no or yes), aspirin use (no or yes), and send deprivation index, family history of not appreciably alter after further ad- nonaspirin NSAID use (no or yes). To diabetes, aspirin use, nonaspirin NSAID justment for vitamin supplement use and evaluate interactions between glucos- use, osteoarthritis or joint pain, hyper- nonvitamin supplement use (HR 0.83, amine use and potential T2D risk factors, tension, high cholesterol, vitamin supple- 95% CI 0.78–0.89) (Table 2). CRP levels and T2D-GRS, multiplicative ment use, nonvitamin supplement use, Similarassociationsofglucosamineuse interaction was assessed by adding in- and fasting hours (except for HbA1c anal- with risk of incident T2D were observed teraction terms to the Cox models. ysis), glucosamine use showed slightly if we further excluded participants with In sensitivity analyses, we first addressed the issues of potential undiagnosed dia- betes at baseline by removing participants Table 1—Basic characteristics of participants by use of glucosamine in the UK Biobank cohort with HbA1c levels $48 mmol/mol (6.5%) or glucose levels $7.0 mmol/L and repeated Glucosamine nonuser Glucosamine user the main analyses. Second, to minimize the Participants 325,920 (80.6) 78,588 (19.4) influence of reverse causation, we also Age, years, mean (SD) 55.1 (8.2) 58.6 (7.2) did a sensitivity analysis by excluding Women 174,537 (53.6) 49,587 (63.1) participants with limited follow-up years White ethnicity 306,882 (94.2) 75,446 (96.0) # ( 2 years). Third, to minimize the in- BMI, kg/m2 fluence of other regular inflammatory ,18.5 1,856 (0.6) 301 (0.4) drug use, we also did a sensitivity analysis 18.5–24.9 111,539 (34.2) 26,756 (34.0) by excluding participants who regularly 25–29.9 140,213 (43.0) 34,550 (44.0) took an anti-inflammatory drug. Fourth, $30 72,312 (22.2) 16,981 (21.6) we also further adjustedfor glucose levels, MET $600 min/week 257,650 (79.1) 65,379 (83.2) Current smoker 36,740 (11.3) 5,097 (6.5) HbA1c levels, or CRP levels in the multi- variable model. Finally,because the status Moderate drinker 149,088 (45.7) 37,534 (47.8) of glucosamine might have changed in the Healthy diet 196,821 (60.4) 55,946 (71.2) follow-up period, we further evaluated Family history of diabetes 67,284 (20.6) 15,615 (19.9) the association of habitual glucosamine Townsend deprivation index, mean (SD) 21.3 (3.1) 21.8 (2.8) use with risk of T2D. Regular anti-inflammatory drugs use All statistical analyses were conducted Aspirin 26,634 (8.2) 7,810 (9.9) using SAS 9.4 software (SAS Institute) and Nonaspirin NSAIDs 47,967 (14.7) 15,253 (19.4) SPSS 22.0 software. All statistical tests Supplement use were two sided, and we considered P , Vitamin supplements 85,241 (26.2) 43,695 (55.6) 0.05 to be statistically significant. Mineral supplements 95,090 (29.1) 54,424 (69.3) Other diseases status History of osteoarthritis or joint pain 46,118 (14.2) 24,287 (30.9) Data and Resource Availability Hypertension 161,476 (49.5) 40,892 (52.0) The genetic and phenotypic UK Biobank High cholesterol 37,595 (11.5) 10,309 (13.1) data are available on application to the Data are n (%) unless otherwise indicated. UK Biobank (www.ukbiobank.ac.uk/). 722 Glucosamine Inversely Associated With T2D Diabetes Care Volume 43, April 2020

glucose levels $7.0 mmol/L or participants Interaction Between Glucosamine Use adjustment for all of the variables listed in with HbA1c levels $48 mmol/mol (6.5%) or and CRP Levels on Risk of T2D Table 1, the first 10 genetic principal excluded participants with limited follow- We also examined the interaction be- components, and genotyping array, higher up years (#2 years), or excluded participants tween glucosamine use and CRP levels on T2D-GRS was significantly associated with who regularly took anti-inflammatory risk of T2D. After adjustment for cova- increased risk of incident T2D (the HR of drugs or further adjusted for glucose riates, including age, sex, race, BMI, as- T2D comparing extreme quartiles was levels, HbA1c levels, or CRP levels (Supple- sessment center, physical activity, smoking 2.27 [95% CI 2.11–2.46]) (Supplementary mentary Tables 4–8). status, moderate drinking, healthy diet, Table 3). We also evaluated the associations of Townsend deprivation index, family his- In the joint analysis, glucosamine use habitual glucosamine use with risk of tory of diabetes, aspirin use, nonaspirin was significantly associated with risk of T2D. We conducted these analyses in NSAID use, osteoarthritis or joint pain, T2D independent of T2D-GRS.We did not participants who provided information in hypertension, high cholesterol, vitamin find significant interaction between glu- the “Vitamin/mineral supplements yes- supplement use, and nonvitamin supple- cosamine use and T2D-GRS on the risk of terday” questionnaire at leastonce during ment use, the baseline CRP level (mg/L) T2D (P-interaction 5 0.99) (Fig. 2B). the follow-up period. After participants was significantly lower in glucosamine who developed T2D before the last sur- users than in nonusers (b 520.02, vey were excluded, a higher degree of P , 0.001). We found that the inverse CONCLUSIONS habitual glucosamine was associated associations between glucosamine use In this prospective study, we observed withalowerriskof T2D(P-trend,0.001). and risk of T2D were more pronounced that habitual use of glucosamine, a In the multivariable-adjusted analyses, in participants with high CRP levels than in widely used supplement for relieving compared with nonglucosamine users, those with low CRP levels. Glucosamine osteoarthritis and joint pain, was asso- the HR was 0.85 (95% CI 0.73–0.99) for use was associated with an 18.8% de- ciated with a 17% lower risk of incident participants who indicated they took creased risk in participants with the high- T2D. This association was independent glucosamine only once at baseline or est quartile of CRP levels. The interaction of traditional risk factors for T2D, socio- during the follow-up (one baseline sur- between glucosamine use and CRP levels economic factors, and use of other vey 1 four times of “Vitamin/mineral on the risk of T2D was statistically signif- supplements. supplements yesterday” surveys); the HR icant (P-interaction 5 0.02) (Fig. 2A). To the best of our knowledge, the was 0.75 (0.63–0.88) for participants Similar interaction patterns were ob- current study is the first to investigate who indicated they took glucosamine served if we further excluded participants the association of glucosamine use with at least two times at baseline or during with a high level of glucose ($7.0 mmol/L), risk of incident T2D in a prospective co- the follow-up period (Supplementary or participants with a high level of HbA1c hort. Of note, several previous studies Table 9). To evaluate whether T2D risk ($48 mmol/mol [6.5%]), or participants showed that short-term administration factors modify the relation between with limited follow-up years (#2years)(P- of high-dose glucosamine had adverse glucosamine use and risk of T2D, we interaction 5 0.04, P-interaction 5 0.02, effects on glucose tolerance and insulin performed stratified analyses according and P-interaction 5 0.03, respectively) sensitivity in animals or humans (6–8,28). to the potential T2D risk factors. We (Supplementary Fig. 1A–C). However, after However, a group of clinical trials found did not find significant interactions be- excluding 96,136 participants who took that long-term glucosamine use did not tween glucosamine use and these risk any other anti-inflammatory drugs, the show adverse effects on glucose metab- factors on risk of incident T2D. Because P value for interaction did not reach the olism in both healthy individuals and the inverse association might be due to significant level (P-interaction 5 0.09) patients with diabetes at the oral dose an overall healthier lifestyle in glucos- (Supplementary Fig. 1D). level (9–12,29). On the contrary, in a amine users, we also examined the in- long-term controlled trial that involved teraction between the overall healthy life Interaction Between Glucosamine Use 212 participants with arthritis, glucos- scoreandglucosamineuseanddidnotfinda and T2D-GRS on Risk of T2D amineproducedaslightlyglucose-lowering significant interaction (P-interaction 50.78) The genetic data were available for effect in participants who received a (Fig. 1). 360,550 participants in this study. After 3-year intervention (13). Similar results were observed in a meta-analysis of the clinical trials (30). Consistent with this finding, we found in the current study — Table 2 HRs of glucosamine use for T2D in the UK Biobank that habitual glucosamine use was slightly Nonglucosamine user Glucosamine user P value associated with lower levels of glucose at Cases, n (%) 5,930 (1.8) 1,298 (1.7) baseline. The contradictory results be- Age- and sex-adjusted HR (95% CI) 1 [Reference] 0.82 (0.77–0.87) ,0.001 tween animal and human studies may Model 1 1 [Reference] 0.81 (0.76–0.86) ,0.001 be partly because the dosages of glucos- Model 2 1 [Reference] 0.83 (0.78–0.89) ,0.001 amineusedinanimalstudiesweremuch – Model1: Resultswereadjustedfor age,sex, race,center,BMI,physicalactivity, smoking, moderate higher (100 200 times) than the usual oral drinking, healthy diet, Townsend deprivation index, aspirin use, nonaspirin NSAID use, family dosage in humans (30). history of diabetes, osteoarthritis or joint pain, hypertension, and high cholesterol. Model 2: Even though the biological mecha- further adjustment for vitamin supplement use and mineral supplement use on the basis of nisms underlying the inverse association model 1. of glucosamine use with risk of T2D care.diabetesjournals.org Ma and Associates 723

Figure 1—Adjusted HR (95% CI) for the use of glucosamine supplements and risk of T2D stratified by potential risk factors. Results were adjusted for age, sex, race,center,BMI,physicalactivity, smoking, healthy diet,moderatedrinking,Townsenddeprivationindex,aspirinuse, nonaspirinNSAIDuse, family history of diabetes, osteoarthritis or joint pain, hypertension, high cholesterol, vitamin supplement use, and mineral supplement use. remain to be explored, several lines of glucosamine has anti-inflammatory proper- circulating levels of CRP, a marker of low- evidence support the potentially protective ties (14,15). Consistent with a previous study grade systemic inflammation, were signifi- effects of glucosamine on the disease. First, in the National Health and Nutrition Exam- cantly lower in glucosamine users compared several previous studies have shown that ination Survey (NHANES) (31), we found that with nonglucosamine users. A randomized 724 Glucosamine Inversely Associated With T2D Diabetes Care Volume 43, April 2020

Figure 2—The joint association of glucosamine use and quartiles of CRP (A) and T2D-GRS (B) in relation to risk of T2D. Results were adjusted for age, sex,race(onlyforA),center,BMI,physicalactivity,smoking, healthydiet,Townsenddeprivationindex,moderatedrinking,aspirinuse,nonaspirinNSAID use, family history of diabetes, osteoarthritis or joint pain, hypertension, high cholesterol, vitamin supplement use and mineral supplement use, the first 10 genetic principal components (only for B), and genotyping array (only for B).

clinical trial also demonstrated that glucos- consistent among people with different on results. Fourth, some incident T2D amine and chondroitin use significantly genetic makeups. cases were diagnosed by the secondary reduced circulating CRP concentrations The major strengths of this study in- diagnosis, thus the incident time of T2D compared with the placebo group (32). clude the large sample size, the well- that was used in this study may be later Given the detrimental roles of inflammation validated measures of biomarkers, and than the actual onset time in this study. in the development of diabetes (17,18), we the consistent results in several sensitiv- However, similar results were observed if assumed that glucosamine might lower the ity analyses. Several potential limitations logistical models were used (odds ratio risk of T2D at least partly through its anti- should be carefully considered in this 0.83, 95% CI 0.78–0.89). Finally, because inflammatory effect. Interestingly, our find- study. First, we could not exclude the of the observational nature of this study, ings showed that the inverse association of possibility that glucosamine use is a causalitycouldnotbederivedinourstudy, glucosamine use with risk of T2D tended marker for a healthy lifestyle. However, and randomized clinical trials are needed to be stronger in participants with higher we carefully controlled for lifestyle factors to verify our findings. baseline CRP levels, and a suggestive in- and did not find any significant modifica- Our findings indicate that habitual teraction between glucosamine use and tion of lifestyle factors on the association glucosamine use, a common supplement baseline CRP levels was observed. These of glucosamine use with risk of T2D, used for osteoarthritis and joint pain, is results lend support to our postulation, suggesting that the observed association associated with a lower risk of T2D. These whereas further studies are needed to of glucosamine use with risk of T2D was findings provide support that glucos- verify these findings. Second, a previous lesslikelyduetoitscorrelationwiththe amine may act as a potential supplement animal study showed that glucosamine healthier lifestyle. Second, our results re- for preventing T2D. Further clinical trials could improve blood glucose levels and garding the interaction of glucosamine are needed to test this hypothesis. extend life span through decreasing gly- and CRP should be interpreted with cau- colysis and increasing amino acid catabo- tion. We could not rule out the possibility lism, and this process was described as that these results were due to chance. The Funding. L.Q. was supported by grants from the mimicking a low-carbohydrate diet (33). A study useda single measurementof CRP at National Heart, Lung, andBlood Institute (HL-071981, low-carbohydrate diet has been associated baseline, which might only reflect short- HL-034594, HL-126024) and the National Institute with lower risk of T2D in previous studies, term inflammation status, and other in- of Diabetes and Digestive and Kidney Diseases probably due to itsdirect impact on glucose flammatory markers should be assessed (DK-115679, DK-091718, DK-100383, DK-078616). – This study was conducted using the UK Biobank metabolism (34 38). Other mechanisms in further studies. In addition, we did not resource, approved project number 29256. may be also involved, and future studies observe the stronger inverse associations Duality of Interest. No potential conflicts of are needed to explore the functional roles in other high inflammation statuses, such interest relevant to this article were reported. of glucosamine in glucose metabolism. as smoking and obesity. Third, some Author Contributions. H.M. performed the Consistent with a previous study (39), detailed information on glucosamine use, statistical analysis. H.M. and L.Q. contributed to the concept and design; acquired, analyzed, or T2D-GRS was significantly positively as- such as the dosage, the formulation (i.e., interpreted the data; and drafted the manu- sociated with incident T2D in our study. some glucosamine supplements contain script. All authors contributed to critical revision However, we did not observe significant chondroitin, methyl-sulfonyl-methane, of the manuscript for important intellectual interaction between glucosamine use or others), and the duration of glucos- content. L.Q. attests that all listed authors meet authorship criteria and that no others and T2D-GRS on the risk of incident T2D, amine use was not collected in this meeting the criteria have been omitted. L.Q. suggesting that the potentially beneficial study. Further studies are warranted is the guarantor of this work and, as such, had full effects of glucosamine on T2D might be to evaluate the effects of these factors access to all the data in the study and takes care.diabetesjournals.org Ma and Associates 725

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