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High-Coverage Targeted Lipidomics Reveals Novel Serum Lipid Predictors and Lipid Pathway Dysregulation Antecedent to Type 2 Diabetes Onset in Normoglycemic Chinese Adults

期刊: DIABETES CARE, 2019; 42 (11)

OBJECTIVE Comprehensive assessment of serum lipidomic aberrations before type 2 diabetes mellitus (T2DM) onset has remained lacking in Han Chinese. We evaluated changes in lipid coregulation antecedent to T2DM and identified novel lipid predictors for T2DM in individuals with normal glucose regulation (NGR). RESEARCH DESIGN AND METHODS In the discovery study, we tested 667 baseline serum lipids in subjects with incident diabetes and propensity score-matched control subjects (n = 200) from a prospective cohort comprising 3,821 Chinese adults with NGR. In the validation study, we tested 250 lipids in subjects with incident diabetes and matched control subjects (n = 724) from a pooled validation cohort of 14,651 individuals with NGR covering five geographical regions across China. Differential correlation network analyses revealed perturbed lipid coregulation antecedent to diabetes. The predictive value of a serum lipid panel independent of serum triglycerides and 2-h postload glucose was also evaluated. RESULTS At the level of false-discovery rate <0.05, 38 lipids, including triacylglycerols (TAGs), lyso-phosphatidylinositols, phosphatidylcholines, polyunsaturated fatty acid (PUFA)-plasmalogen phosphatidylethanolamines (PUFA-PEps), and cholesteryl esters, were significantly associated with T2DM risk in the discovery and validation cohorts. A preliminary study found most of the lipid predictors were also significantly associated with the risk of prediabetes. Differential correlation network analysis revealed that perturbations in intraclass (i.e., non-PUFA-TAG and PUFA-TAGs) and interclass (i.e., TAGs and PUFA-PEps) lipid coregulation preexisted before diabetes onset. Our lipid panel further improved prediction of incident diabetes over conventional clinical indices. CONCLUSIONS These findings revealed novel changes in lipid coregulation existing before diabetes onset and expanded the current panel of serum lipid predictors for T2DM in normoglycemic Chinese individuals.

IF:15.27

From Hong Kong Diabetes Register to JADE Program to RAMP-DM for Data-Driven Actions

期刊: DIABETES CARE, 2019; 42 (11)

In 1995, the Hong Kong Diabetes Register (HKDR) was established by a doctor-nurse team at a university-affiliated, publicly funded, hospital-based diabetes center using a structured protocol for gathering data to stratify risk, triage care, empower patients, and individualize treatment. This research-driven quality improvement program has motivated the introduction of a territory-wide diabetes risk assessment and management program provided by 18 hospital-based diabetes centers since 2000. By linking the data-rich HKDR to the territory-wide electronic medical record, risk equations were developed and validated to predict clinical outcomes. In 2007, the HKDR protocol was digitalized to establish the web-based Joint Asia Diabetes Evaluation (JADE) Program complete with risk levels and algorithms for issuance of personalized reports to reduce clinical inertia and empower self-management. Through this technologically assisted, integrated diabetes care program, we have generated big data to track secular trends, identify unmet needs, and verify interventions in a naturalistic environment. In 2009, the JADE Program was adapted to form the Risk Assessment and Management Program for Diabetes Mellitus (RAMP-DM) in the publicly funded primary care clinics, which reduced all major events by 30-60% in patients without complications. Meanwhile, a JADE-assisted assessment and empowerment program provided by a university-affiliated, self-funded, nurse-coordinated diabetes center, aimed at complementing medical care in the community, also reduced all major events by 30-50% in patients with different risk levels. By combining universal health coverage, public-private partnerships, and data-driven integrated care, the Hong Kong experience provides a possible solution than can be adapted elsewhere to make quality diabetes care accessible, affordable, and sustainable.

IF:15.27

Metabolically Healthy Obesity and High Carotid Intima-Media Thickness in Children and Adolescents: International Childhood Vascular Structure Evaluation Consortium

期刊: DIABETES CARE, 2019; 42 (1)

OBJECTIVE It has been argued that metabolically healthy obesity (MHO) does not increase cardiovascular disease (CVD) risk. This study examines the association of MHO with carotid intima-media thickness (cIMT), a proxy of CVD risk, in children and adolescents. RESEARCH DESIGN AND METHODS Data were available for 3,497 children and adolescents aged 6-17 years from five population-based cross-sectional studies in Brazil, China, Greece, Italy, and Spain. Weight status categories (normal, overweight, and obese) were defined using BMI cutoffs from the International Obesity Task Force. Metabolic status (defined as "healthy" [no risk factors] or "unhealthy" [one or more risk factors]) was based on four CVD risk factors: elevated blood pressure, elevated triglyceride levels, reduced HDL cholesterol, and elevated fasting glucose. High cIMT was defined as cIMT >= 90th percentile for sex, age, and study population. Logistic regression model was used to examine the association of weight and metabolic status with high cIMT, with adjustment for sex, age, race/ethnicity, and study center. RESULTS In comparison with metabolically healthy normal weight, odds ratios (ORs) for high cIMT were 2.29 (95% CI 1.58-3.32) for metabolically healthy overweight and 3.91 (2.46-6.21) for MHO. ORs for high cIMT were 1.44 (1.03-2.02) for unhealthy normal weight, 3.49 (2.51-4.85) for unhealthy overweight, and 6.96 (5.05-9.61) for unhealthy obesity. CONCLUSIONS Among children and adolescents, cIMT was higher for both MHO and metabolically healthy overweight compared with metabolically healthy normal weight. Our findings reinforce the need for weight control in children and adolescents irrespective of their metabolic status.

IF:15.27

Real-World Database Examining the Association Between Avascular Necrosis of the Femoral Head and Diabetes in Taiwan

期刊: DIABETES CARE, 2019; 42 (1)

OBJECTIVE No study has been conducted to evaluate the association between avascular necrosis of the femoral head and diabetes. This study's aim was to assess this issue in Taiwan. RESEARCH DESIGN AND METHODS A population-based cohort study was performed to analyze the database of Taiwan's National Health Insurance Program. There were 27,869 subjects aged 20-84 years with newly diagnosed diabetes from 2000 to 2012 as the group with diabetes. The group without diabetes included 111,476 sex-and age-matched subjects without diabetes. The incidence of avascular necrosis of the femoral head at the end of 2013 was measured. A multivariable Cox proportional hazards regression model was used to measure the hazard ratio (HR) and 95% CI for avascular necrosis of the femoral head associated with diabetes. RESULTS The overall incidence of avascular necrosis of the femoral head was 1.37-fold higher in the group with diabetes than in the group without diabetes (6.53 vs. 4.76 per 1,000 person-years [95% CI 1.31-1.43]). After adjusting for confounders, the HR of avascular necrosis of the femoral head was 1.16 (95% CI 1.11-1.21) for the subjects with diabetes compared with the subjects without diabetes. CONCLUSIONS Patients with diabetes have a 1.16-fold increased risk for developing avascular necrosis of the femoral head.

IF:15.27

Visit-to-Visit Fasting Glucose Variability in Young Adulthood and Hippocampal Integrity and Volume at Midlife

期刊: DIABETES CARE, 2019; 42 (12)

OBJECTIVE To determine whether visit-to-visit fasting glucose (VVFG) variability in young adulthood is associated with midlife hippocampal integrity and volume. RESEARCH DESIGN AND METHODS Multivariable-adjusted linear regression models were used to estimate the association between VVFG variability and brain MRI variables in 543 CARDIA study participants. VVFG variability was defined by the SD of FG (SDFG), the coefficient of variation of the mean FG (CVFG), and the average real variability (ARV(FG)) over 25 years of follow-up. Hippocampal integrity fractional anisotropy (FA) and tissue volume standardized to intracranial volume were measured by 3T MRI at year 25. RESULTS After multivariable adjustment, higher FG variability (1-SD increase) was associated with lower hippocampal FA (SDFG -0.015 [95% CI -0.026, -0.004]; CVFG -0.009 [95% CI -0.018, -0.001]; ARV(FG) -0.011 [95% CI -0.019, -0.002]) and lower hippocampal volume (SDFG -0.012 [95% CI -0.023, -0.001]). CONCLUSIONS Higher VVFG variability in young adulthood is associated with lower midlife hippocampal integrity and volume, suggesting its value in predicting risk for hippocampal structural damage.

IF:15.27

Sex Differences in Cardiovascular Risk Profile From Childhood to Midlife Between Individuals Who Did and Did Not Develop Diabetes at Follow-up: The Bogalusa Heart Study

期刊: DIABETES CARE, 2019; 42 (4)

OBJECTIVE Childhood and young adulthood may represent time periods in which cardiovascular risk factors (CVRFs) and their cumulative exposure lay the foundation for future risk of chronic diseases. We examined the longitudinal burden of CVRFs since childhood in men and women in whom diabetes did and did not develop at follow-up. RESEARCH DESIGN AND METHODS We included 1,530 participants (mean [SD] follow-up time 33.1 [8.2] years), who participated in the Bogalusa Heart Study and had been examined at least four times starting in childhood (mean age [SD] at first examination 9.4 [3.1] years). The area under the growth curve was used as a measure of cumulative exposure to CVRFs since childhood. RESULTS In childhood, boys and girls in whom diabetes did and did not develop at follow-up had similar CVRFs. Yet, over time, women during the transition from normoglycemia to diabetes experienced greater adverse changes in total cholesterol (TC), LDL cholesterol, and fasting plasma glucose (FPG) (noted as early as 23.5 years old and persisting across adulthood up to the age of the diagnosis of diabetes); a higher burden of exposure to BMI, TC, LDL cholesterol, and FPG from childhood to midlife; and a greater change in rates of BMI, TC, LDL cholesterol, and FPG since childhood than men during the same transition (interaction P values <0.05). CONCLUSIONS The greater exposure of women to and burden of CVRFs associated with diagnosis of diabetes may help to explain the stronger impact of diabetes as a major risk factor for cardiovascular events in women compared with men.

IF:15.27

Comparative Effects of Proximal and Distal Small Intestinal Glucose Exposure on Glycemia, Incretin Hormone Secretion, and the Incretin Effect in Health and Type 2 Diabetes

期刊: DIABETES CARE, 2019; 42 (4)

OBJECTIVE Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-O-methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic clamp studies were performed on the other two days. Blood glucose, serum 3-O-methylglucose, and plasma hormones were evaluated over 180 min. RESULTS In both groups, blood glucose and serum 3-O-methylglucose concentrations were higher after proximal than distal glucose infusion (all P < 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P < 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P <= 0.009). CONCLUSIONS The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM.

IF:15.27

Frailty and Risk of Fractures in Patients With Type 2 Diabetes

期刊: DIABETES CARE, 2019; 42 (4)

OBJECTIVE We aimed to explore whether frailty was associated with fracture risk and whether frailty could modify the propensity of type 2 diabetes toward increased risk of fractures. RESEARCH DESIGN AND METHODS Data were from a prospective cohort study. Our primary outcome was time to the first incident clinical fragility fracture; secondary outcomes included time to hip fracture and to clinical spine fracture. Frailty status was measured by a Frailty Index (FI) of deficit accumulation. The Cox model incorporating an interaction term (frailty x diabetes) was used for analyses. RESULTS The analysis included 3,149 (70% women) participants; 138 (60% women) had diabetes. Higher bone mineral density and FI were observed in participants with diabetes compared with control subjects. A significant relationship between the FI and the risk of incident fragility fractures was found, with a hazard ratio (HR) of 1.02 (95% CI 1.01-1.03) and 1.19 (95% CI 1.10-1.33) for per-0.01 and per-0.10 FI increase, respectively. The interaction was also statistically significant (P = 0.018). The HR for per-0.1 increase in the FI was 1.33 for participants with diabetes and 1.19 for those without diabetes if combining the estimate for the FI itself with the estimate from the interaction term. No evidence of interaction between frailty and diabetes was found for risk of hip and clinical spine fractures. CONCLUSIONS Participants with type 2 diabetes were significantly frailer than individuals without diabetes. Frailty increases the risk of fragility fracture and enhances the effect of diabetes on fragility fractures. Particular attention should be paid to diabetes as a risk factor for fragility fractures in those who are frail.

IF:15.27

Predicting Islet Cell Autoimmunity and Type 1 Diabetes: An 8-Year TEDDY Study Progress Report

期刊: DIABETES CARE, 2019; 42 (6)

OBJECTIVEAssessment of the predictive power of The Environmental Determinants of Diabetes in the Young (TEDDY)-identified risk factors for islet autoimmunity (IA), the type of autoantibody appearing first, and type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSA total of 7,777 children were followed from birth to a median of 9.1 years of age for the development of islet autoantibodies and progression to T1D. Time-dependent sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated to provide estimates of their individual and collective ability to predict IA and T1D.RESULTSHLA genotype (DR3/4 vs. others) was the best predictor for IA (Youden's index J = 0.117) and single nucleotide polymorphism rs2476601, in PTPN22, was the best predictor for insulin autoantibodies (IAA) appearing first (IAA-first) (J = 0.123). For GAD autoantibodies (GADA)-first, weight at 1 year was the best predictor (J = 0.114). In a multivariate model, the area under the ROC curve (AUC) was 0.678 (95% CI 0.655, 0.701), 0.707 (95% CI 0.676, 0.739), and 0.686 (95% CI 0.651, 0.722) for IA, IAA-first, and GADA-first, respectively, at 6 years. The AUC of the prediction model for T1D at 3 years after the appearance of multiple autoantibodies reached 0.706 (95% CI 0.649, 0.762).CONCLUSIONSPrediction modeling statistics are valuable tools, when applied in a time-until-event setting, to evaluate the ability of risk factors to discriminate between those who will and those who will not get disease. Although significantly associated with IA and T1D, the TEDDY risk factors individually contribute little to prediction. However, in combination, these factors increased IA and T1D prediction substantially.

IF:15.27

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