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Investigators of previous cross-sectional epigenome-wide association studies (EWAS) in adults have reported hundreds of 5′-cytosine-phosphate-guanine-3′ (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWAS have been inconsistent, and longitudinal observations of these associations are scarce. Furthermore, few studies have investigated whether DNA methylation (DNAm) could be modified by smoking, drinking, and glycemic traits, which have broad impacts on genome-wide DNAm and result in altering the risk of T2DM. Twin studies provide a valuable tool for epigenetic studies, as twins are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and Embase for EWAS, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c, and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17, and 16 CpG sites from previous studies were validated for T2DM, HbA1c, and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 for 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. A total of 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none were from the other cross-lagged direction, indicating that CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed to explore the mediation effects of DNAm on the associations of smoking, drinking, and glycemic traits with T2DM. No significant mediations of DNAm in the associations linking smoking and drinking with T2DM were found. In contrast, our study suggested a potential role of DNAm of cg19693031, cg00574958, and cg04816311 in mediating the effect of altered glycemic traits on T2DM.

OBJECTIVE Type 2 diabetes is related to obesity and altered bone health, and both are affected by gut microbiota. We examined associations of weight loss diet–induced changes in a gut microbiota–related metabolite trimethylamine N-oxide (TMAO), and its precursors (choline and l-carnitine), with changes in bone mineral density (BMD) considering diabetes-related factors. RESEARCH DESIGN AND METHODS In the 2-year Preventing Overweight Using Novel Dietary Strategies trial (POUNDS Lost), 264 overweight and obese participants with measurement of BMD by DXA scan were included in the present analysis. The participants were randomly assigned to one of four diets varying in macronutrient intake. Association analysis was performed in pooled participants and different diet groups. Changes in blood levels of TMAO, choline, and l-carnitine from baseline to 6 months after the dietary intervention were calculated. RESULTS We found that a greater reduction in plasma levels of TMAO from baseline to 6 months was associated with a greater loss in whole-body BMD at 6 months and 2 years (P = 0.03 and P = 0.02). The greater reduction in TMAO was also associated with a greater loss in spine BMD (P = 0.005) at 2 years, independent of body weight changes. The associations were not modified by baseline diabetes status and glycemic levels. Changes in l-carnitine, a precursor of TMAO, showed interactions with dietary fat intake in regard to changes of spine BMD and hip BMD at 6 months (all P < 0.05). Participants with the smallest decrease in l-carnitine showed less bone loss in the low-fat diet group than the high-fat diet group (Pspine = 0.03 and Phip = 0.02). CONCLUSIONS TMAO might protect against BMD reduction during weight loss, independent of diet interventions varying in macronutrient content and baseline diabetes risk factors. Dietary fat may modify the relation between change in plasma l-carnitine level and changes in BMD. Our findings highlight the importance of investigating the relation between TMAO and bone health in patients with diabetes.

OBJECTIVE Adiposity and the gut microbiota are both related to the risk of type 2 diabetes. We aimed to comprehensively examine how changes induced by a weight-loss diet intervention in gut microbiota–related metabolites, such as trimethylamine N-oxide (TMAO) and its precursors (choline and l-carnitine), were associated with improvements in adiposity and regional fat deposition. RESEARCH DESIGN AND METHODS This study included 510 overweight and obese individuals who were randomly assigned one of four diets varying in macronutrient intake. We examined associations of 6-month changes in blood metabolites (TMAO, choline, and l-carnitine) with improvements in body weight (BW), waist circumference (WC), body fat composition, fat distribution, and resting energy expenditure (REE). RESULTS Individuals with a greater reduction of choline (P < 0.0001) and l-carnitine (P < 0.01) rather than TMAO showed significant losses of BW and WC at 6 months. The reduction of choline was significantly predictive of decreases in body fat composition, fat distribution, and REE. Results of sensitivity analysis showed that the baseline diabetes risk status, such as the presence of hyperglycemia (31% of the total participants) and fasting glucose levels, did not modify the associations. Early changes in choline and l-carnitine were significantly predictive of weight loss over 2 years (P < 0.05 for all). Individuals with increases in choline or l-carnitine were 2.35-times (95% CI 1.38, 4.00) or 1.77-times (1.06, 2.95) more likely to fail to lose weight (–5% or more loss) at 2 years. CONCLUSIONS Overweight and obese individuals who showed decreases in circulating choline or l-carnitine levels achieved greater improvements of adiposity and energy metabolism by eating a low-calorie weight-loss diet, suggesting that such metabolites are predictive of individuals’ response to the treatment. Further investigations are necessary to confirm our findings, particularly in a population with prediabetes that is more representative of the U.S. population with obesity.

Whether change in physical activity over time modifies the genetic susceptibility to long-term weight gain is unknown. We calculated a BMI–genetic risk score (GRS) based on 77 BMI-associated single nucleotide polymorphisms (SNPs) and a body fat percentage (BF%)-GRS based on 12 BF%-associated SNPs in 9,390 women from the Nurses’ Health Study (NHS) and 5,291 men from the Health Professionals Follow-Up Study (HPFS). We analyzed the interactions between each GRS and change in physical activity on BMI/body weight change within five 4-year intervals from 1986 to 2006 using multivariable generalized linear models with repeated-measures analyses. Both the BMI-GRS and the BF%-GRS were associated with long-term increases in BMI/weight, and change in physical activity consistently interacted with the BF%-GRS on BMI change in the NHS (P for interaction = 0.025) and HPFS (P for interaction = 0.001). In the combined cohorts, 4-year BMI change per 10-risk allele increment was −0.02 kg/m2 among participants with greatest increase in physical activity and 0.24 kg/m2 among those with greatest decrease in physical activity (P for interaction < 0.001), corresponding to 0.01 kg versus 0.63 kg weight changes every 4 years (P for interaction = 0.001). Similar but marginal interactions were observed for the BMI-GRS (P for interaction = 0.045). Our data indicate that the genetic susceptibility to weight gain may be diminished by increasing physical activity.

Salivary and pancreatic amylases (encoded by AMY1 and AMY2 genes, respectively) are responsible for digesting starchy foods. AMY1 and AMY2 show copy number variations that affect differences in amylase amount and activity, and AMY1 copies have been associated with adiposity. We investigated whether genetic variants determining amylase gene copies are associated with 2-year changes in adiposity among 692 overweight and obese individuals who were randomly assigned to diets varying in macronutrient content. We found that changes in body weight (BW) and waist circumference (WC) were significantly different according to the AMY1-AMY2 rs11185098 genotype. Individuals carrying the A allele (indicating higher amylase amount and activity) showed a greater reduction in BW and WC at 6, 12, 18, and 24 months than those without the A allele (P < 0.05 for all). The association was stronger for long-term changes compared with short-term changes of these outcomes. The genetic effects on these outcomes did not significantly differ across diet groups. In conclusion, the genetic variant determining starch metabolism influences the response to weight-loss dietary intervention. Overweight and obese individuals carrying the AMY1-AMY2 rs11185098 genotype associated with higher amylase activity may have greater loss of adiposity during low-calorie diet interventions.

Prenatal exposure to maternal smoking (MS) and genetic predisposition to obesity have been related to an increased risk of developing type 2 diabetes (T2D), individually; however, little is known about whether these risk factors may interact with each other. This study included 394867 European participants in UK Biobank. Three types of adiposity polygenetic score (PGS) were created based on 97, 66, and 12 genetic loci associated with BMI, waist-to-hip ratio adjusted for BMI (WHRadjBMI), and percentage of body fat (PBF). The adjusted odds ratio (OR) of MS for T2D was 1.25 (95% CI: 1.21-1.28), and ORs for T2D were 1.09 (1.08-1.11), 1.07 (1.05-1.08), and 1.02 (1.01-1.04) per one SD increment of BMI-, WHRadjBMI-, and PBF- PGS. The joint associations of MS and a higher adiposity genetic susceptibility for T2D were 1.52 (1.45-1.60), 1.43 (1.36-1.50), and 1.35 (1.28-1.41), respectively. The estimated proportions of the joint association were 45.1% for MS alone, 28.4% for genetic susceptibility to obesity alone, and 26.5% for their additive interaction. Our results indicate that the increased risk of T2D due to the joint association of MS and adiposity genetic predisposition was greater than each factor. Our findings extend our knowledge on the synergistic contribution of prenatal factors and genetic make-up to adiposity on T2D risk, and re-emphasize the importance of smoking cessation around pregnancy in women. Disclosure D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. L. Qi: None. Funding National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK078616); Boston Nutrition Obesity Research Center (DK46200); United States-Israel Binational Science Foundation (2011036)

Background: Recent evidence has related high levels of plasma branch-chained amino acids (BCAAs) with liver and visceral fat. We examined the associations of plasma BCAAs with liver fat and abdominal fat distribution and assessed the potential modification of weight-loss diet interventions on these relations. Methods: The current study included 184 participants with available data on plasma BCAAs, hepatic fat and abdominal fat distribution over 2 years, who were randomly assigned to 1 of 4 diets varying in macronutrient components. Results: Decrease in plasma BCAAs after weight loss was significantly associated with improvement in hepatic density (a marker for hepatic fat; p=0.03) and reduction in visceral fat (p=0.01). We also found that a decrease in BCAAs was associated with decreased insulin, HOMA-IR, and triglycerides (p Conclusion: Our findings indicate that weight-loss diets decrease BCAAs, which are in turn associated with the reduction of hepatic and visceral fat. Finally, dietary protein modifies the direction of these associations. Disclosure X. Li: None. D. Sun: None. T. Zhou: None. G. Bray: Advisory Panel; Self; Herbalife International of America, Inc., Medifast. F. Sacks: None. L. Qi: None. Funding National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616); Boston Nutrition Obesity Research Center (DK46300); United States-Israel Binational Science Foundation (2011036); American Heart Association (0730094N to L.Q.)

Lower educational attainment has been associated with an increased risk of obesity; however, the causality of educational attainment in relation to adiposity, body composition, and fat distribution remains to be established. We used two-sample Mendelian randomization (MR) analyses of summary statistics with participants number ranged from 330,762 to 1,131,881 to test the causal effects of educational attainment in body fatness phenotypes [e.g., BMI, body fat mass, and waist-to-hip ratio (WHR)]. A total of 1,196 available single nucleotide polymorphisms associated with educational attainment were included in the current analysis. Eight complementary MR methods were used to test the robustness of our results. The genetically-instrumented higher educational attainment was consistently associated with a lower BMI [β -0.42, 95% confidence interval (CI) -0.45 to -0.39], body fat percentage (-0.31, -0.33 to -0.28), body fat mass (-0.36, -0.39 to -0.33), and waist circumference (-0.31, -0.33 to -0.28). The causal relationships of higher educational attainment with lower body weight, fat-free mass, and hip circumference were less consistent. There was no causal relation between educational attainment and WHR (Figure 1). In conclusion, our findings indicate low educational attainment may causally increase BMI, body fat and waist circumference. Disclosure T. Zhou: None. D. Sun: None. X. Li: None. Y. Heianza: None. L. Qi: None. Funding National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616); Boston Obesity Nutrition Research Center (DK46300); United States-Israel Binational Science Foundation (20110360); American Heart Association (0730094N to L.Q.)

Zinc transporter 8 genetic variant SLC30A8 has been associated with postpartum risk of type 2 diabetes among women with gestational diabetes mellitus (GDM). Gestational weight gain is one of the strongest risk factors for postpartum hyperglycemia. We assessed the interaction between type 2 diabetes–associated SLC30A8 rs13266634 and gestational weight gain on 1–5 years of postpartum glycemic changes in 1,071 women with prior GDM in a longitudinal study. Compared with gestation of 26–30 weeks, postpartum levels of fasting glucose, oral glucose tolerance test 2-h glucose, and hemoglobin A1c (HbA1c) increased across rs13266634 TT, CT, and CC genotypes in women with excessive gestational weight gain, whereas opposite genetic associations were found in women with inadequate or adequate gestational weight gain. Postpartum changes in fasting glucose per additional copy of the C allele were −0.18, −0.04, and 0.12 mmol/L in women with inadequate, adequate, and excessive gestational weight gain, respectively (P for interaction = 0.002). We also found similar interactions for changes in 2-h glucose and HbA1c (P for interaction = 0.003 and 0.005, respectively). Our data indicate that gestational weight gain may modify SLC30A8 variant on long-term glycemic changes, highlighting the importance of gestational weight control in the prevention of postpartum hyperglycemia in women with GDM.

Type 2 diabetes is one of the most common chronic diseases in the U.S.; however, few studies have comprehensively assessed the relations between its comorbidities and premature death. Prospective analyses were performed linking data from National Health Interview Surveys (1997 to 2009) to National Death Index records (2011) among 366,971 adults. Cox models were used to test the relations of diabetes and eleven comorbidities with all-cause, CVD, or cancer mortality. After a median follow-up of 8.0 years (2.9 million person-years), a total of 38,687 participants had died. Compared with common-conditions-free subjects, we ranked hazard ratios (HR[95% CI]) of eleven diabetic comorbidities, and the top three were chronic kidney disease (CKD: 5.3[4.9-5.7]), liver cirrhosis (5.1[4.6-5.8]), and blindness (4.4[3.8-5.1]) for all-cause mortality. Diabetics with CKD (5.9[5.0-6.9]) and blindness (5.0[3.8-6.5]) were at the highest risk for CVD deaths. Comorbid cancer (4.1[3.6-4.6]), liver cirrhosis (4.1[3.2-5.2]), and hepatitis (2.7[2.1-3.5]) ranked top three for cancer mortality. Diabetes comorbidities may substantially increase the risk of all-cause, CVD, or cancer mortality. Liver disease is more strongly related to cancer mortality, whereas CKD and blindness with CVD. Recognition of these associations may assist with more appropriate and effective screening programs that may help decrease associated mortality. Disclosure D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. X. Shang: None. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. L. Qi: None.

Gestational diabetes mellitus (GDM) is a common medical complication in pregnancy, carries adverse health outcomes for both mothers and offspring. However, national data on the prevalence and secular trends of GDM during the past 10 years in the U.S. is lacking. This study included 26,340 ever-pregnant women aged ≥ 18 years from the National Health Interview Survey in 20and 2016. We examined GDM prevalence in 20and 2016. The prevalence of GDM increased from 4.6% in 20to 8.2% in 2016 (P In conclusion, the prevalence of GDM increased by 3.6% from 20to 2016; and the rise was more marked among non-white, overweight, low income, age 45-64 years, and insufficient activity groups. Disclosure T. Zhou: None. D. Sun: None. X. Li: None. Y. Heianza: None. H. Nisa: None. G. Hu: None. X. Pei: None. X. Shang: None. L. Qi: None.

Diabetes affected over 30 million U.S. adults in 2015, and its comorbidities remained among the leading causes of premature death and reduced quality of life. However, little is known about the secular trend of diabetes comorbidities in the last 20 years. Sample-weighted prevalence of twelve common comorbidities of diabetes was estimated using data from 52,842 adults aged ≥18 years who had diabetes in the National Health Interview Survey from 1997 through 2016, with age-standardized to the 2000 U.S. population. We ranked the prevalence [% (SE)] of twelve diabetes comorbidities, and the top five were hypertension [53.7(3.1)], arthritis [33.2(3.1)], asthma [17.2(2.9)], coronary heart disease [CHD: 14.4(2.3)]), and chronic obstructive pulmonary disease [COPD: 9.1(2.3)]. From 1997 to 2016, the estimated prevalence (%) of diabetes comorbidities including hypertension (47.8 to 59.7), asthma (13.2 to 21.0), cancer (7.6 to 10.4), and liver cirrhosis (3.0 to 4.1) continuingly increased (P Disclosure D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. X. Shang: None. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. L. Qi: None.

Gut microbiota alterations may be related to insulin resistance, diabetes, and the impaired amino acid metabolism. We investigated whether changes in gut microbiota metabolite of trimethylamine N-oxide (TMAO) and its precursors (choline and L-carnitine) were associated with improvements of diabetes-related traits and diabetes-risk-related amino acids in a weight-loss diet intervention. This study included 504 obese adults who were randomly assigned to 1 of 4 energy-reduced diets varying in the macronutrient composition. We calculated changes (Δ) in TMAO, choline, and L-carnitine from baseline to 6 months after the diet intervention. Greater decreases in choline and L-carnitine were significantly (p In conclusion, weight-loss-diet-induced changes in TMAO, choline, and L-carnitine were significantly associated with the improvements in glycemia and insulin sensitivity, regardless concurrent changes in diabetes-risk related amino acids. Dietary fat intake may modify the associations of changes in TMAO with the improvements of diabetes-related traits. Disclosure Y. Heianza: None. D. Sun: None. G. Bray: Advisory Panel; Self; Herbalife International of America, Inc., Novo Nordisk A/S. L. Qi: None.