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The trans-ancestral genomic architecture of glycemic traits.
Chen, J, Spracklen, CN, Marenne, G, Varshney, A, Corbin, LJ, Luan, J, Willems, SM, Wu, Y, Zhang, X, Horikoshi, M, et al
Nature genetics. 2021;(6):840-860
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Abstract
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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C-R Relationship between Fasting Plasma Glucose and Unfavorable Outcomes in Patients of Ischemic Stroke withoutDiabetes.
Xing, L, Liu, S, Tian, Y, Yan, H, Jing, L, Chen, K, Yan, F, Li, Y, Lv, J, Sun, Y
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2019;(5):1400-1408
Abstract
BACKGROUND Limited data are available on the impact of fasting plasma glucose (FPG) on outcomes in nondiabetic acute ischemic stroke patients. METHODS The prospective, multi-center, and observational study was performed at 8 hospitals in the Liaoning Province between 2015-2016, sought to elucidate the relationship between FPG and the 6-month functional outcomes in nondiabetic acute ischemic stroke patients. The primary effect measure was the adjusted odds ratio for a shift in the direction of unfavorable outcome on the modified Rankin Scale (mRS) score at 6 months, estimated with an ordinal logistic regression, and adjusted for common prognostic factors. Finally, we employed a restricted cubic spline function of linear model to characterize concentration-response (C-R) relationships between FPG and outcomes. RESULTS A total of 1260 consecutive patients were enrolled, 48.9% of patients had FPG levels >6.1mmol/L. A total of 282 (22.4%) patients achieved an unfavorable neurologic outcome. Patients achieving an unfavorable neurologic outcome had significantly higher levels of FPG than those achieving a favorable neurologic outcome (6.47mmol/L versus 7.02 mmol/L). FPG was significantly related to an unfavorable neurologic outcome in nondiabetic acute ischemic stroke patients. The C-R curve showed a nonlinear relation between FPG and 6-month mRS with the nadir at 5.9mmol/L. Moreover, the likelihood of unfavorable outcome increased by 8.5% for each 1mmol/L increase in FPG. CONCLUSIONS Early identification and prompt hyperglycemia management should be considered to improve the functional outcomes during the early poststroke stage.
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Elevated fasting serum glucose levels increase the risk of hepatocellular carcinoma: A prospective cohort study.
Liu, T, Wang, W, Cui, H, Sun, M, Wang, Y, Liu, X, Cao, L, Liu, H, Liu, S
Medicine. 2019;(30):e16369
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Abstract
Previous studies have demonstrated a positive relationship between liver cancer and diabetes mellitus. However, elevated fasting blood glucose (FBG) itself may be a risk factor for the development of hepatocellular carcinoma (HCC) rather than diabetes, and during the follow-up period, death is an event that may occur before the occurrence of HCC, which should be dealt with competing risk models. Our study aims to investigate the relationship between FBG and new-onset HCC by using competing risk regression models.We prospectively studied the relationship between FBG concentrations and risk of HCC in a cohort of 93,447 participants who were free of prior HCC, and whose demographic characteristics and biochemical parameters were recorded. Cox proportional hazards regression models and competing risk regression models were used to evaluate the association between FBG concentrations and risk of incident HCC.A total of 302 participants were diagnosed with HCC among 93,447 subjects during 810,499 person-years of follow-up. The multivariable hazard ratios (HRs) [95% confidence interval (95% CI)] for the association of FBG and log(FBG) with HCC were 1.07 (1.01∼1.12), 1.84 (1.23∼2.74) in an analysis adjusted for other potential variables. In the multivariable adjusted analysis, participants who were in 4.82 mmol/L≤FBG≤5.49 mmol/L group and FBG >5.49 mmol/L group would have increased the risk of HCC by 47% and 69%, respectively. In a cause-specific hazard model (CS model), the multivariable HRs (95% CI) for the association of FBG with HCC were 1.46 (1.09∼1.98), 1.69 (1.27∼2.27) in the multivariable adjusted analysis. Similar results were also observed in sub-distribution hazard function model (SD model) with corresponding multivariate HRs (95% CI) of 1.46 (1.09∼2.00), 1.69 (1.25∼2.27) in 4.82 mmol/L≤FBG≤5.49 mmol/L group and FBG >5.49 mmol/L group, respectively.Higher FBG concentrations itself were positively associated with new-onset HCC in the Cox proportional hazards regression models and competing risk models. FBG concentrations can be used as a scientific and important way to identify individuals with a higher risk of HCC and control of FBG concentrations might serve as a possible way to decrease the risk of HCC among Chinese population.Trial registration: ChiCTR-TNRC-11001489. Registered August 24, 2011 (retrospectively registered).
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Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes: A Systematic Review and Updated Meta-Analyses of Prospective Cohort Studies.
Livesey, G, Taylor, R, Livesey, HF, Buyken, AE, Jenkins, DJA, Augustin, LSA, Sievenpiper, JL, Barclay, AW, Liu, S, Wolever, TMS, et al
Nutrients. 2019;(6)
Abstract
Published meta-analyses indicate significant but inconsistent incident type-2 diabetes(T2D)-dietary glycemic index (GI) and glycemic load (GL) risk ratios or risk relations (RR). It is nowover a decade ago that a published meta-analysis used a predefined standard to identify validstudies. Considering valid studies only, and using random effects dose-response meta-analysis(DRM) while withdrawing spurious results (p < 0.05), we ascertained whether these relationswould support nutrition guidance, specifically for an RR > 1.20 with a lower 95% confidence limit>1.10 across typical intakes (approximately 10th to 90th percentiles of population intakes). Thecombined T2D-GI RR was 1.27 (1.15-1.40) (p < 0.001, n = 10 studies) per 10 units GI, while that forthe T2D-GL RR was 1.26 (1.15-1.37) (p < 0.001, n = 15) per 80 g/d GL in a 2000 kcal (8400 kJ) diet.The corresponding global DRM using restricted cubic splines were 1.87 (1.56-2.25) (p < 0.001, n =10) and 1.89 (1.66-2.16) (p < 0.001, n = 15) from 47.6 to 76.1 units GI and 73 to 257 g/d GL in a 2000kcal diet, respectively. In conclusion, among adults initially in good health, diets higher in GI or GLwere robustly associated with incident T2D. Together with mechanistic and other data, thissupports that consideration should be given to these dietary risk factors in nutrition advice.Concerning the public health relevance at the global level, our evidence indicates that GI and GLare substantial food markers predicting the development of T2D worldwide, for persons ofEuropean ancestry and of East Asian ancestry.
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Relationship between dietary carbohydrates intake and circulating sex hormone-binding globulin levels in postmenopausal women.
Huang, M, Liu, J, Lin, X, Goto, A, Song, Y, Tinker, LF, Chan, KK, Liu, S
Journal of diabetes. 2018;(6):467-477
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BACKGROUND Low circulating levels of sex hormone-binding globulin (SHBG) have been shown to be a direct and strong risk factor for type 2 diabetes, cardiovascular diseases, and hormone-dependent cancers, although the relationship between various aspects of dietary carbohydrates and SHBG levels remains unexplored in population studies. METHODS Among postmenopausal women with available SHBG measurements at baseline (n = 11 159) in the Women's Health Initiative, a comprehensive assessment was conducted of total dietary carbohydrates, glycemic load (GL), glycemic index (GI), fiber, sugar, and various carbohydrate-abundant foods in relation to circulating SHBG levels using multiple linear regressions adjusting for potential covariates. Linear trend was tested across quartiles of dietary variables. Benjamini and Hochberg's procedure was used to calculate the false discovery rate for multiple comparisons. RESULTS Higher dietary GL and GI (both based on total and available carbohydrates) and a higher intake of sugar and sugar-sweetened beverages were associated with lower circulating SHBG concentrations (all P trend < 0.05; Q -values = 0.04,0.01, 0.07, 0.10, 0.01, and <0.0001, respectively). In contrast, women with a greater intake of dietary fiber tended to have elevated SHBG levels (P trend = 0.01, Q -value = 0.04). There was no significant association between total carbohydrates or other carbohydrate-abundant foods and SHBG concentrations. CONCLUSIONS The findings suggest that low GL or GI diets with low sugar and high fiber content may be associated with higher serum SHBG concentrations among postmenopausal women. Future studies investigating whether lower GL or GI diets increase SHBG concentrations are warranted.
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Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
Liu, CT, Raghavan, S, Maruthur, N, Kabagambe, EK, Hong, J, Ng, MC, Hivert, MF, Lu, Y, An, P, Bentley, AR, et al
American journal of human genetics. 2016;(1):56-75
Abstract
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
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Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies.
Livesey, G, Taylor, R, Livesey, H, Liu, S
The American journal of clinical nutrition. 2013;(3):584-96
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BACKGROUND Although much is known about the association between dietary glycemic load (GL) and type 2 diabetes (T2D), prospective cohort studies have not consistently shown a positive dose-response relation. OBJECTIVE We performed a comprehensive examination of evidence on the dose response that links GL to T2D and sources of heterogeneity among all prospective cohort studies on healthy adults available in the literature. DESIGN We conducted a systematic review of all prospective cohort studies and meta-analyses to quantify the GL-T2D relation both without and with adjustment for covariates. RESULTS Among 24 prospective cohort studies identified by August 2012, the GL ranged from ∼60 to ∼280 g per daily intake of 2000 kcal (8.4 MJ). In a fully adjusted meta-analysis model, the GL was positively associated with RR of T2D of 1.45 (95% CI: 1.31, 1.61) for a 100-g increment in GL (P < 0.001; n = 24 studies; 7.5 million person-years of follow-up). Sex (P = 0.03), dietary instrument validity (P < 0.001), and ethnicity (European American compared with other; P = 0.04) together explained 97% of the heterogeneity among studies. After adjustment for heterogeneities, we used both funnel and trim-and-fill analyses to identify a negligible publication bias. Multiple influence, cumulative, and forecast analyses indicated that the GL-T2D relation tended to have reached stability and to have been underestimated. The relation was apparent at all doses of GL investigated, although it was statistically significant only at >95 g GL/2000 kcal. CONCLUSION After we accounted for several sources of heterogeneity, findings from prospective cohort studies that related the GL to T2D appear robust and consistently indicate strong and significantly lower T2D risk in persons who consume lower-GL diets. This review was registered at http://www.crd.york.ac.uk/PROSPERO as CRD42011001810.
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Effects of a low-fat dietary intervention on glucose, insulin, and insulin resistance in the Women's Health Initiative (WHI) Dietary Modification trial.
Shikany, JM, Margolis, KL, Pettinger, M, Jackson, RD, Limacher, MC, Liu, S, Phillips, LS, Tinker, LF
The American journal of clinical nutrition. 2011;(1):75-85
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BACKGROUND Glycemic effects of the Women's Health Initiative (WHI) low-fat dietary intervention are unknown. OBJECTIVE Our objective was to analyze the effects of the WHI low-fat dietary intervention on serum glucose and insulin and insulin resistance up to 6 y after random assignment. DESIGN Postmenopausal WHI Dietary Modification trial intervention (DM-I) and comparison (DM-C) participants with blood measures at least at baseline and year 1 (n = 2263) were included. Anthropometric measures, dietary assessments, serum glucose and insulin concentrations, homeostasis model assessment of insulin resistance (HOMA-IR) measures, and quantitative insulin sensitivity check index (QUICKI) values were obtained at baseline, year 1, year 3, and year 6. Changes in measures were compared between groups at years 1, 3, and 6 overall and within stratified analyses. RESULTS Mean (±SD) differences in changes at year 1 between the DM-I and DM-C groups were as follows: glucose, -1.7 ± 17.9 mg/dL; insulin, -0.7 ± 5.1 μIU/mL; HOMA-IR, -0.2 ± 1.9; and QUICKI, 0.004 ± 0.019 (all P < 0.05). Similar findings resulted from repeated-measures analyses comparing the intervention and comparison groups over the 6 y. Whereas normoglycemic women at baseline had a decrease in glucose at year 1 that was 1.9 ± 17.2 mg/dL greater in the DM-I than in the DM-C group, diabetic women had an increase in glucose that was 7.9 ± 20.3 mg/dL greater in the DM-I than in the DM-C group (P for interaction <0.001). CONCLUSIONS A low-fat diet was not significantly associated with adverse glycemic effects up to 6 y after random assignment in postmenopausal women. However, diabetic women experienced adverse glycemic effects of the low-fat diet. This trial is registered at clinicaltrials.gov as NCT00000611.
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Informing food choices and health outcomes by use of the dietary glycemic index.
Chiu, CJ, Liu, S, Willett, WC, Wolever, TM, Brand-Miller, JC, Barclay, AW, Taylor, A
Nutrition reviews. 2011;(4):231-42
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Considerable epidemiologic evidence links consuming lower glycemic index (GI) diets with good health, particularly upon aging. The GI is a kinetic parameter that reflects the ability of carbohydrate (CHO) contained in consumed foods to raise blood glucose in vivo. Newer nutritional, clinical, and experimental data link intake of lower dietary GI foods to favorable outcomes of chronic diseases, and compel further examination of the record. Based upon the new information there are two specific questions: 1) should the GI concept be promoted as a way to prolong health, and 2) should food labels contain GI information? Further, what are the remaining concerns about methodological issues and consistency of epidemiological data and clinical trials that need to be resolved in order to exploit the benefits of consuming lower GI diets? These issues are addressed in this review.
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Effects of oral magnesium supplementation on glycaemic control in Type 2 diabetes: a meta-analysis of randomized double-blind controlled trials.
Song, Y, He, K, Levitan, EB, Manson, JE, Liu, S
Diabetic medicine : a journal of the British Diabetic Association. 2006;(10):1050-6
Abstract
AIMS: The aim of this study was to assess the evidence on the effect of oral magnesium supplementation on glycaemic control in patients with Type 2 diabetes. METHODS We searched the electronic databases of medline, embase and the Cochrane Controlled Trials Register up to January 2005. We identified nine randomized double-blind controlled trials with a total of 370 patients with Type 2 diabetes and of duration 4-16 weeks. The median dose of oral magnesium supplementation was 15 mmol/day (360 mg/day) in the treatment groups. The primary outcome was glycaemic control, as measured by glycated haemoglobin (HbA(1c)) or fasting blood glucose levels; the secondary outcomes included body mass index, blood pressure (BP) and lipids. Using a random-effects model, we calculated the weighted mean differences (WMD) and 95% confidence interval (CI). RESULTS After a median duration of 12 weeks, the weighted mean post-intervention fasting glucose was significantly lower in the treatment groups compared with the placebo groups [-0.56 mmol/l (95% CI, -1.10 to -0.01); P for heterogeneity = 0.02]. The difference in post-intervention HbA(1c) between magnesium supplementation groups and control groups was not significant [-0.31% (95% CI, -0.81 to 0.19); P for heterogeneity = 0.10]. Neither systolic nor diastolic BP was significantly changed. Magnesium supplementation increased on high-density lipoprotein (HDL) cholesterol levels [0.08 mmol/l (95% CI, 0.03 to 0.14); P for heterogeneity = 0.36] but had no effect on total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride. CONCLUSIONS Oral magnesium supplementation for 4-16 weeks may be effective in reducing plasma fasting glucose levels and raising HDL cholesterol in patients with Type 2 diabetes, although the long-term benefits and safety of magnesium treatment on glycaemic control remain to be determined.