Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase ~50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Association of adherence to a Mediterranean diet with glycemic control and cardiovascular risk factors in youth with type I diabetes: the SEARCH Nutrition Ancillary Study.

BACKGROUND/OBJECTIVES: This study aimed to determine the association between a Mediterranean diet and glycemic control and other cardiovascular risk factors among youth with type I diabetes (TID). SUBJECTS/METHODS: Incident TID cases aged <20 years at diagnosis between 2002 and 2005 were included. Participants were seen at baseline (N=793), 1-year (N=512) and 5-year follow-up visits (N=501). Mediterranean diet score was assessed using a modified KIDMED index (mKIDMED). Multivariate linear regression and longitudinal mixed model were applied to determine the association between mKIDMED score and log-HbA1c, lipids, blood pressure (BP) and obesity. RESULTS: In cross-sectional analyses using baseline data, for individuals with the hemoglobin A1c (HbA1c) of 7.5%, a two-point higher mKIDMED score (1 s.d.) was associated with 0.15% lower HbA1c (P=0.02). A two-point higher mKIDMED score was associated with 4.0 mg/dl lower total cholesterol (TC) (P=0.006), 3.4 mg/dl lower low-density lipoprotein cholesterol (LDL-C) (P=0.004), 3.9 mg/dl lower non-high-density lipoprotein cholesterol (non-HDL-C) (P=0.004) and 0.07 lower LDL-C/HDL-C ratio (P=0.02). Using longitudinal data, a two-point increase in mKIDMED score was associated with 0.01% lower log-HbA1c (P=0.07), 1.8 mg/dl lower TC (P=0.05), 1.6 mg/dl lower LDL-C (P=0.03) and 1.8 mg/dl lower non-HDL-C (P=0.03) than would otherwise have been expected. HbA1c mediated ∼20% of the association for lipids in both cross-sectional and longitudinal models. An unexpected positive association between mKIDMED score and systolic BP was found among non-Hispanic white youth in cross-sectional analyses (P=0.009). Mediterranean diet was not associated with obesity. CONCLUSIONS: Mediterranean diet may improve glycemic control and cardiovascular health in TID youth.

Biomarkers associated with severe hypoglycaemia and death in ACCORD.

AIMS AND HYPOTHESIS: In patients with Type 2 diabetes, intensive glycaemic control is associated with hypoglycaemia and possibly increased mortality. However, no blood biomarkers exist to predict these outcomes. Using participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesized that insulin deficiency and islet autoantibodies in patients with clinically diagnosed Type 2 diabetes would be associated with severe hypoglycaemia and death. METHODS: A nested case-control study design was used. A case (n = 86) was a participant who died with at least one episode of severe hypoglycaemia, defined as hypoglycaemia requiring assistance, at any point during ACCORD follow-up. A control (n = 344) was a participant who did not die and did not have severe hypoglycaemia during follow-up. Each case was matched to four controls (glycaemic intervention arm, race, age and BMI). Baseline insulin deficiency (fasting C-peptide ≤ 0.15 nmol/l) and islet autoantibodies [glutamic acid decarboxylase (GAD), tyrosine phosphatase-related islet antigen 2 (IA2), insulin (IAA) and zinc transporter (ZnT8)] were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used. RESULTS: Death during ACCORD in those who experienced at least one episode of severe hypoglycaemia was associated with insulin deficiency [OR 4.8 (2.1, 11.1): P < 0.0001], GAD antibodies [OR 2.3 (1.1, 5.1): P = 0.04], the presence of IAA or baseline insulin use [OR 6.1 (3.5,10.7): P < 0.0001], which remained significant after adjusting for age, BMI, and diabetes duration. There was no significant association with IA2 or ZnT8 antibodies. CONCLUSIONS: In patients with Type 2 diabetes, C-peptide or GAD antibodies may serve as blood biomarkers predicting higher odds of subsequent severe hypoglycaemia and death. (Clinical Trial Registry No: NCT00000620, www.clinicaltrials.gov for original ACCORD study).

Adiponectin, C-reactive protein, fibrinogen and tissue plasminogen activator antigen levels among glucose-intolerant women with and without histories of gestational diabetes.

AIM: To examine concentrations of biomarkers (adiponectin, C-reactive protein, fibrinogen and tissue plasminogen-activator antigen) associated with glucose homeostasis and diabetes risk by history of gestational diabetes (GDM). METHODS: We conducted a secondary analysis of the Diabetes Prevention Program, a randomized trial of lifestyle intervention or metformin for diabetes prevention. At baseline, participants were overweight and had impaired glucose tolerance. Biomarkers at baseline and 1 year after enrolment were compared between parous women with (n = 350) and without histories of GDM (n = 1466). Cox proportional hazard models evaluated whether history of GDM was associated with diabetes risk, after adjustment for baseline biomarker levels as well as for change in biomarker levels, demographic factors and anthropometrics. RESULTS: At baseline, women with histories of GDM had lower adiponectin (7.5 µg/ml vs. 8.7 µg/ml; p < 0.0001) and greater log C-reactive protein (-0.90 mg/l vs. -0.78 mg/l, p = 0.04) levels than women without histories of GDM, but these associations did not persist after adjustment for demographic factors. Fibrinogen and tissue plasminogen-activator antigen were similar between women with and without histories of GDM. Women with and without histories of GDM had a similar pattern of changes in biomarkers within randomization arm. Adjustment for age, race/ethnicity, baseline weight, change in weight, baseline biomarker level and change in biomarker level did not significantly alter the association between history of GDM, and diabetes risk. CONCLUSIONS: Among women with impaired glucose tolerance, biomarkers in women with and without histories of GDM are similar and respond similarly to lifestyle changes and metformin. Adjustment for biomarker levels did not explain the higher risk of diabetes observed in women with histories of GDM.

Flexible Lifestyles for Youth (FL3X) behavioural intervention for at-risk adolescents with Type 1 diabetes: a randomized pilot and feasibility trial.

AIM: To determine the potential effect sizes for the Flexible Lifestyle for Youth (FL3X) behavioural intervention to improve glycaemic control (HbA(1c)) and quality of life for at-risk adolescents with Type 1 diabetes. METHODS: Participants [n = 61; age 12-16 years, HbA(1c) 64-119 mmol/mol (8-13%)] were randomized to FL3X (minimum three sessions) or usual care. Effect sizes (Cohen's d), comparing the mean difference between the groups, were calculated. RESULTS: Study retention (95%), attendance at intervention sessions (87% attended all three sessions) and acceptability were high (100% of the adolescents and 91% of parents would recommend the programme to others). Overall, 41% of participants in the intervention group and 24% of participants in the control group were 'responders' [HbA(1c) decreased by > 6 mmol/mol (0.5%); d = 0.37]. HbA(1c) levels decreased (d = -0.18), diabetes-specific quality of life increased (d = 0.29), but generic quality of life decreased (d = -0.23) in the intervention compared with the control group. CONCLUSIONS: The FL3X programme merits further study for improving HbA(1c) and diabetes-specific quality of life in adolescents with Type 1 diabetes. (Clinical trials registry no.: NCT01286350).

Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program.

AIMS: To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program. METHODS: A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes. RESULTS: The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA(1c), estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56-1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%). CONCLUSIONS: These data suggest that 'diabetes autoimmunity', as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes.

Metabolic syndrome components and their response to lifestyle and metformin interventions are associated with differences in diabetes risk in persons with impaired glucose tolerance.

AIMS: To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. METHODS: We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. RESULTS: In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3-2.3), 1.7 (1.2-2.3) and 2.0 (1.3-3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. CONCLUSIONS: MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence.

Vitamin D in youth with Type 1 diabetes: prevalence of insufficiency and association with insulin resistance in the SEARCH Nutrition Ancillary Study.

AIMS: To determine the prevalence of plasma vitamin D (25-dihydroxyvitamin D) insufficiency in individuals with Type 1 diabetes and to determine the cross-sectional and longitudinal associations of plasma vitamin D with insulin resistance. METHODS: Participants from the SEARCH for Diabetes in Youth Study [n = 1426; mean age 11.2 years (sd 3.9)] had physician-diagnosed Type 1 diabetes [diabetes duration mean 10.2 months (sd 6.5)] with data available at baseline and follow-up (approximately 12 and 24 months after baseline). Insulin resistance was estimated using a validated equation. Cross-sectional and longitudinal multivariate logistic regression models were used to determine the association of plasma vitamin D with insulin resistance, adjusting for potential confounders. RESULTS: Forty-nine per cent of individuals had plasma vitamin D < 50 nmol/l and 26% were insulin resistant. In cross-sectional multivariate analyses, participants who had higher plasma vitamin D (65 nmol/l) had lower odds of prevalent insulin resistance than participants with lower plasma vitamin D (25 nmol/l) (odds ratio 0.70, 95% CI 0.57-0.85). This association was attenuated after additional adjustment for BMI z-score, which could be a confounder or a mediator (odds ratio 0.81, 95% CI 0.64-1.03). In longitudinal multivariate analyses, individuals with higher plasma vitamin D at baseline had lower odds of incident insulin resistance, but this was not significant (odds ratio 0.85, 95% CI 0.63-1.14). CONCLUSIONS: Vitamin D insufficiency is common in individuals with Type 1 diabetes and may increase risk for insulin resistance. Additional prospective studies are needed to determine the association between plasma vitamin D and insulin resistance, and to further examine the role of adiposity on this association.

Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program.

CONTEXT: Although intensive lifestyle change (ILS) and metformin reduce diabetes incidence in subjects with impaired glucose tolerance (IGT), their effects on lipoprotein subfractions have not been studied. OBJECTIVE: The objective of the study was to characterize the effects of ILS and metformin vs placebo interventions on lipoprotein subfractions in the Diabetes Prevention Program. DESIGN: This was a randomized clinical trial, testing the effects of ILS, metformin, and placebo on diabetes development in subjects with IGT. PARTICIPANTS: Selected individuals with IGT randomized in the Diabetes Prevention Program participated in the study. INTERVENTIONS: Interventions included randomization to metformin 850 mg or placebo twice daily or ILS aimed at a 7% weight loss using a low-fat diet with increased physical activity. MAIN OUTCOME MEASURES: Lipoprotein subfraction size, density, and concentration measured by magnetic resonance and density gradient ultracentrifugation at baseline and 1 year were measured. RESULTS: ILS decreased large and buoyant very low-density lipoprotein, small and dense low-density lipoprotein (LDL), and small high-density lipoprotein (HDL) and raised large HDL. Metformin modestly reduced small and dense LDL and raised small and large HDL. Change in insulin resistance largely accounted for the intervention-associated decreases in large very low-density lipoprotein, whereas changes in body mass index (BMI) and adiponectin were strongly associated with changes in LDL. Baseline and a change in adiponectin were related to change in large HDL, and BMI change associated with small HDL change. The effect of metformin to increase small HDL was independent of adiponectin, BMI, and insulin resistance. CONCLUSION: ILS and metformin treatment have favorable effects on lipoprotein subfractions that are primarily mediated by intervention-related changes in insulin resistance, BMI, and adiponectin. Interventions that slow the development of diabetes may also retard the progression of atherosclerosis.

Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study.

AIMS: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group. METHODS: This long-term follow-up (median 10 years, interquartile range 9.0-10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually. RESULTS: After 10 years' follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (-2 to -3) and diastolic (-6 to -6.5 mmHg) blood pressure, and for LDL cholesterol (-0.51 to -0.6 mmol/l) and triglycerides (-0.23 to -0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study. CONCLUSION: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups.

Clinical evolution of beta cell function in youth with diabetes: the SEARCH for Diabetes in Youth study.

AIMS/HYPOTHESIS: Few studies have explored the epidemiology of beta cell loss in youth with diabetes. This report describes the evolution and major determinants of beta cell function, assessed by fasting C-peptide (FCP), in the SEARCH for Diabetes in Youth study. METHODS: Participants were 1,277 youth with diabetes (948 positive for diabetes autoantibodies [DAs] and 329 negative for DAs), diagnosed when aged <20 years, who were followed from a median of 8 months post diagnosis, for approximately 30 months. We modelled the relationship between rate of change in log FCP and determinants of interest using repeated measures general linear models. RESULTS: Among DA-positive youth, there was a progressive decline in beta cell function of 4% per month, independent of demographics (age, sex, race/ethnicity), genetic susceptibility to autoimmunity (HLA risk), HbA(1c) and BMI z score, or presence of insulin resistance. Among DA-negative youth, there was marked heterogeneity in beta cell loss, reflecting an aetiologically mixed group. This group likely includes youths with undetected autoimmunity (whose decline is similar to that of DA-positive youth) and youth with non-autoimmune, insulin-resistant diabetes, with limited decline (~0.7% per month). CONCLUSIONS/INTERPRETATION: SEARCH provides unique estimates of beta cell function decline in a large sample of youth with diabetes, indicating that autoimmunity is the major contributor. These data contribute to a better understanding of clinical evolution of beta cell function in youth with diabetes, provide strong support for the aetiological classification of diabetes type and may inform tertiary prevention efforts targeted at high-risk groups.

Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience.

AIMS/HYPOTHESIS: Fenofibrate has been noted to cause an elevation in serum creatinine in some individuals. Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes. METHODS: A fenofibrate-associated creatinine increase (FACI) was defined as an increase in serum creatinine of at least 20% from baseline to month 4 in participants assigned to fenofibrate. Baseline patient characteristics, and baseline and 4-month drug, clinical, laboratory characteristics and study outcomes were examined by FACI status. RESULTS: Of the sample, 48% of those randomised to receive fenofibrate had at least a 20% increase in serum creatinine within 4 months. In multivariable analysis, participants who were older, male, used an ACE inhibitor at baseline, used a thiazolidinedione (TZD) at 4 months post-randomisation, had baseline CVD, and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI. Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months. No differences in study outcomes were seen by FACI criteria. CONCLUSIONS/INTERPRETATION: Several characteristics predict a rapid rise in serum creatinine upon starting fenofibrate. Participants who met the criteria for FACI also had a greater change in triacylglycerol levels. In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated, no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI. TRIAL REGISTRATION: ClincalTrials.gov: NCT00000620. FUNDING: The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035 and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; by General Clinical Research Centers and by the Clinical and Translational Science Awards. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis US and Takeda Pharmaceuticals provided study medications, equipment or supplies.

ß-cell autoimmunity in overweight non-diabetic youth: any implications?

BACKGROUND AND OBJECTIVE: The presence of ß-cell antibodies is associated with a high risk of type 1 diabetes. With increasing rates of obesity, the distinction between obese T1DM and T2DM has become difficult. Moreover, increasing body mass index (BMI) in at-risk children has been proposed not only as a possible contributor to T1DM by increasing insulin resistance, but also as exerting an effect via the immunomodulatory properties of certain adipokines. This study aimed to determine prevalence of ß-cell autoantibodies (AA) in overweight non-diabetic children and assess insulin sensitivity and secretion derived from an oral glucose tolerance test (OGTT) in those with vs. without ß-cell AA. RESEARCH DESIGN AND METHODS: A total of 357 overweight (BMI > 85%) youths underwent OGTTs, dual energy X-ray absorptiometry (DEXA) and measurement of GAD65 and IA-2 AA according to the NIDDK harmonization assay. Using the same methodology, AA were measured in 90 normal weight, non-diabetic individuals. RESULTS: About 1.9% of overweight and 4.4% of control normal weight children had evidence of ß-cell autoimmunity, with GAD65 AA detected in all subjects but none with IA-2. Youth with positive vs. those with negative AA had higher leptin/adiponectin ratio, glucose at 60 min and C-peptide at 90 min. CONCLUSIONS: These findings suggest that the prevalence of ß-cell AA in overweight youth may be similar to that in non-overweight children. Further studies using standardized methods are required.

HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion.

AIMS/HYPOTHESIS: We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona. METHODS: Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits. RESULTS: The A allele at rs9268852, which tags HLA-DRB1 02(1602), was associated both with higher HLA-DRB1 mRNA expression (n = 133, p = 4.27 × 10(-14)) and decreased risk of type 2 diabetes (n = 3,265, OR 0.723, p = 0.002). Among persons with normal glucose tolerance (n = 266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p = 0.005), higher mean 30 min insulin concentration during an oral glucose tolerance test (p = 0.017) and higher body fat percentage (p = 0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity. CONCLUSIONS/INTERPRETATION: HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.

Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth.

AIM/HYPOTHESIS: Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been associated with type 2 diabetes in adults. However, it is not known whether TCF7L2 variation increases the risk of early onset type 2 diabetes. Using a case-control design, we examined whether the reported variants [rs12255372 (T/G) and rs7903146 (T/C)] are associated with type 2 diabetes in SEARCH for Diabetes in Youth study participants. METHODS: Variants were genotyped in 694 non-Hispanic white (NHW) youth (86 cases, mean age 15.5 years, mean BMI 34.8; and 608 controls, mean age 14.4 years, mean BMI 22.3) and 545 African-American (AA) youth (154 cases, mean age 15.9, mean BMI 37; and 391 controls, mean age 14.8, mean BMI 23.8). Logistic regression adjusted for age, sex, BMI and West African ancestry. RESULTS: The association of the risk T allele with case/control status was different in AA and NHW youth (p = 0.025). Among AA youth, each copy of the T allele (rs7903146) was associated with a 1.97-fold (1.37, 2.82) increased odds for type 2 diabetes (p < 0.0001), after adjustment for age, sex, BMI and African ancestry. No significant association was detected in NHW youth (adjusted OR, 1.14; 0.73, 1.79). CONCLUSION/INTERPRETATION: TCF7L2 variation is associated with an increased risk of early-onset type 2 diabetes among AA youth, and the association appears to be stronger in AA than NHW youth. This suggests potential different contributions of genetic and environmental factors to early-onset type 2 diabetes by race.

SAA and PLTP activity in plasma of periodontal patients before and after full-mouth tooth extraction.

OBJECTIVE: To assess whether treatment of advanced periodontal disease affects plasma levels of serum amyloid A (SAA) and phospholipid transfer protein (PLTP) activity. DESIGN: We measured the levels of SAA and PLTP activity in plasma of 66 patients with advanced periodontal disease before and after treatment by full-mouth tooth extraction (FME). RESULTS: At baseline, median SAA levels in our study population were within the normal range (2.7 microg ml(-1)) but SAA was elevated (>5 microg ml(-1)) in 18% of periodontitis patients. Three months after FME, SAA levels were significantly reduced (P = 0.04). SAA did not correlate with any of the periodontal disease parameters. PLTP activity was elevated in patients with periodontitis, compared to the PLTP activity reference group (age-matched systemically healthy adults, n = 29; 18 micromol ml(-1) h(-1)vs 13 micromol ml(-1) h(-1), respectively, P = 0.002). PLTP activity inversely correlated with average periodontal pocket depth (PPD) per tooth (r(s) = -0.372; P = 0.002). Three months after FME, median PLTP activity did not change significantly. CONCLUSIONS: Full-mouth tooth extraction significantly reduces SAA, a marker of inflammation, while it does not affect plasma PLTP activity. However, the inverse correlation between PLTP activity and average PPD suggests that increased PLTP activity may limit periodontal tissue damage.

Evidence mounts for a role of the kidney in lipoprotein(a) catabolism.

Numerous studies have suggested a role of the kidney in lipoprotein(a) (Lp(a)) catabolism, but direct evidence is still lacking. Frischmann et al. demonstrate that the marked elevation of Lp(a) observed in hemodialysis patients results from a decrease in Lp(a) clearance rather than an increase in Lp(a) production, consistent with the notion that the kidney degrades Lp(a). More studies are needed to prove the biological relevance.

Biochemical and bioimaging markers for risk assessment and diagnosis in major cardiovascular diseases: a road to integration of complementary diagnostic tools.

This report from the first International Course on Integrated Biomarkers, Biochemical and Bioimaging Endpoints in Cardiovascular Diagnosis, Prevention, Therapy and Drug Development provides the basis for optimizing diagnostic, prognostic and therapeutic information in four areas of cardiovascular medicine: primary prevention of cardiovascular diseases, acute coronary syndromes, heart failure and stroke. Risk stratification and treatment strategies can be refined and enhanced through integration of bioimaging and biochemical markers to characterize sub-clinical and clinical atherosclerosis. For the integrative approach to be useful, each of the biomarkers must be validated and cost-effective. Clinical decision is the primary level of integration and is based on clinical evaluation and the use of a combination of bioimaging and biochemical markers. The decision to initiate preventive or therapeutic intervention must take into account the factors affecting the levels of expression of the biomarker and the potential input the biomarker has on metabolic processes or modulation of other biomarkers. The optimal approach to intervention must take into consideration the risk-benefit and cost-effectiveness ratios.