The association of insulin responses and insulin sensitivity with cognition in adults with pre-diabetes: The Diabetes Prevention Program Outcomes Study.

OBJECTIVE: Dysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant(s) of dysglycemia, impaired insulin sensitivity (ISens) or the islet ß-cell's response (IResp), contribute to poorer cognitive function, independent of dysglycemia is not established. Among 1052 adults with pre-diabetes from the Diabetes Prevention Program Outcomes Study (DPPOS), we investigated the relationship between IResp, ISens and cognitive function. RESEARCH DESIGN AND METHODS: IResp was estimated by the insulinogenic index (IGI; pmol/mmol) and ISens as 1/fasting insulin from repeated annual oral glucose tolerance tests. The mean IResp and mean ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and executive function (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Linear regression models were run for each cognitive outcome and were adjusted for dysglycemia and other factors. RESULTS: Higher IResp was associated with poorer performance on the DSST (-0.69 points per 100 unit increase in IGI, 95 % CI: -1.37, -0.01). ISens was not associated with DSST, nor were IResp or ISens associated with performance on the SEVLT. CONCLUSIONS: These results suggest that a greater ß-cell response in people at high risk for type 2 diabetes is associated with poorer executive function, independent of dysglycemia and ISens.

Persistence of antibody responses to COVID-19 vaccines among participants in the COVID-19 Community Research Partnership.

Introduction: High levels of immunity to SARS-CoV-2 in the community correlate with protection from COVID-19 illness. Measuring COVID-19 antibody seroprevalence and persistence may elucidate the level and length of protection afforded by vaccination and infection within a population. Methods: We measured the duration of detectable anti-spike antibodies following COVID-19 vaccination in a multistate, longitudinal cohort study of almost 13,000 adults who completed daily surveys and submitted monthly dried blood spots collected at home. Results: Overall, anti-spike antibodies persisted up to 284 days of follow-up with seroreversion occurring in only 2.4% of the study population. In adjusted analyses, risk of seroreversion increased with age (adults aged 55-64: adjusted hazard ratio [aHR] 2.19 [95% confidence interval (CI): 1.22, 3.92] and adults aged > 65: aHR 3.59 [95% CI: 2.07, 6.20] compared to adults aged 18-39). Adults with diabetes had a higher risk of seroreversion versus nondiabetics (aHR 1.77 [95% CI: 1.29, 2.44]). Decreased risk of seroreversion was shown for non-Hispanic Black versus non-Hispanic White (aHR 0.32 [95% CI: 0.13, 0.79]); college degree earners versus no college degree (aHR 0.61 [95% CI: 0.46, 0.81]); and those who received Moderna mRNA-1273 vaccine versus Pfizer-BioNTech BNT162b2 (aHR 0.35 [95% CI: 0.26, 0.47]). An interaction between healthcare worker occupation and sex was detected, with seroreversion increased among male, non-healthcare workers. Conclusion: We established that a remote, longitudinal, multi-site study can reliably detect antibody durability following COVID-19 vaccination. The survey platform and measurement of antibody response using at-home collection at convenient intervals allowed us to explore sociodemographic factors and comorbidities and identify predictors of antibody persistence, which has been demonstrated to correlate with protection against disease. Our findings may help inform public health interventions and policies to protect those at highest risk for severe illness and assist in determining the optimal timing of booster doses.Clinical trials registry: NCT04342884.

Reproducibility of Glycemic Measures Among Dysglycemic Youth and Adults in the RISE Study.

AIMS: Previous work found poor reproducibility for measures of glycemia in individuals at risk for dysglycemia. Differences between youth and adults have not been assessed. Using youth and adults in the Restoring Insulin Secretion Study, we tested variability and classification concordance for hemoglobin A1C (HbA1c), fasting and 2-hour glucose from oral glucose tolerance tests (OGTTs). METHODS: HbA1c and glucose on repeated samples obtained ∼6 weeks apart were compared in 66 youth (mean age 14.2 years) and 354 adults (52.7 years). Changes, coefficient of variation (CV), and concordance of diagnostic categories between the 2 visits were compared. RESULTS: Mean difference between the 2 visits in HbA1c was higher in youth than adults (P < .001), while fasting glucose was similar and 2-hour glucose was lower in youth (P = .051). CV was smallest for HbA1c compared to fasting and 2-hour glucose. For HbA1c, youth had higher CV (P < .001); whereas CV for 2-hour glucose was lower for youth (P = .041). Classification concordance by HbA1c was lower in youth (P = .004). Using OGTT or HbA1c for classification, intervisit variability produced discordant classification in 20% of youth and 28% of adults. Using both fasting glucose and HbA1c, intervisit variability reduced discordant classification to 16% of adults while not improving classification in youth. CONCLUSIONS: Poor reproducibility and lack of classification concordance highlight the limitations of one-time testing, with important implications for assessing eligibility in clinical trials. Consideration should be given to using more than a single parameter for screening and diagnosis, especially when classification category is important.

Estimated COVID-19 vaccine effectiveness against seroconversion from SARS-CoV-2 Infection, March-October, 2021.

BACKGROUND: Monitoring the effectiveness of COVID-19 vaccines against SARS-CoV-2 infections remains important to inform public health responses. Estimation of vaccine effectiveness (VE) against serological evidence of SARS-CoV-2 infection might provide an alternative measure of the benefit of vaccination against infection. METHODS: We estimated mRNA COVID-19 vaccine effectiveness (VE) against development of SARS-CoV-2 anti-nucleocapsid antibodies in March-October 2021, during which the Delta variant became predominant. Participants were enrolled from four participating healthcare systems in the United States, and completed electronic surveys that included vaccination history. Dried blood spot specimens collected on a monthly basis were analyzed for anti-spike antibodies, and, if positive, anti-nucleocapsid antibodies. We used detection of new anti-nucleocapsid antibodies to indicate SARS-CoV-2 infection, and estimated VE by comparing 154 case-participants with new detection of anti-nucleocapsid antibodies to 1,540 seronegative control-participants matched by calendar period. Using conditional logistic regression, we estimated VE ≥ 14 days after the 2nd dose of an mRNA vaccine compared with no receipt of a COVID-19 vaccine dose, adjusting for age group, healthcare worker occupation, urban/suburban/rural residence, healthcare system region, and reported contact with a person testing positive for SARS-CoV-2. RESULTS: Among individuals who completed a primary series, estimated VE against seroconversion from SARS-CoV-2 infection was 88.8% (95% confidence interval [CI], 79.6%-93.9%) after any mRNA vaccine, 87.8% (95% CI, 75.9%-93.8%) after BioNTech vaccine and 91.7% (95% CI, 75.7%-97.2%) after Moderna vaccine. VE was estimated to be lower ≥ 3 months after dose 2 compared with < 3 months after dose 2, and among participants who were older or had underlying health conditions, although confidence intervals overlapped between subgroups. CONCLUSIONS: VE estimates generated using infection-induced antibodies were consistent with published estimates from clinical trials and observational studies that used virologic tests to confirm infection during the same period. Our findings support recommendations for eligible adults to remain up to date with COVID-19 vaccination.

Association between COVID-19 and consistent mask wearing during contact with others outside the household-A nested case-control analysis, November 2020-October 2021.

BACKGROUND: Face masks have been recommended to reduce SARS-CoV-2 transmission. However, evidence of the individual benefit of face masks remains limited, including by vaccination status. METHODS: As part of the COVID-19 Community Research Partnership cohort study, we performed a nested case-control analysis to assess the association between self-reported consistent mask use during contact with others outside the household and subsequent odds of symptomatic SARS-CoV-2 infection (COVID-19) during November 2020-October 2021. Using conditional logistic regression, we compared 359 case-participants to 3544 control-participants who were matched by date, adjusting for enrollment site, age group, sex, race/ethnicity, urban/rural county classification, and healthcare worker occupation. RESULTS: COVID-19 was associated with not consistently wearing a mask (adjusted odds ratio [aOR] 1.49; 95% confidence interval [CI] [1.14, 1.95]). Compared with persons ≥14 days after mRNA vaccination who also reported always wearing a mask, COVID-19 was associated with being unvaccinated (aOR 5.94; 95% CI [3.04, 11.62]), not wearing a mask (aOR 1.62; 95% CI [1.07, 2.47]), or both unvaccinated and not wearing a mask (aOR 9.07; 95% CI [4.81, 17.09]). CONCLUSIONS: Our findings indicate that consistent mask wearing can complement vaccination to reduce the risk of COVID-19.

COVID-19 Symptoms by Variant Period in the North Carolina COVID-19 Community Research Partnership, North Carolina, USA.

In North Carolina, USA, the SARS-CoV-2 Omicron variant was associated with changing symptomology in daily surveys, including increasing rates of self-reported cough and sore throat and decreased rates of loss of taste and smell. Compared with the pre-Delta period, Delta and Omicron (pre-BA.4/BA.5) variant periods were associated with shorter symptom duration.

Association between self-reported masking behavior and SARS-CoV-2 infection wanes from Pre-Delta to Omicron-predominant periods - North Carolina COVID-19 Community Research Partnership (NC-CCRP).

BACKGROUND: Wearing a face mask is a primary public health method to reduce SARS-CoV-2 transmission. METHODS: We performed a nested case-control analysis within the North Carolina COVID-19 Community Research Partnership (NC-CCRP) of adults who completed daily surveillance surveys, April 2020 - February 2022. We assessed the association between self-reported mask wearing behavior during nonhousehold interactions and COVID-19 infection during 3 pandemic periods using conditional logistic regression models of risk of infection that were adjusted for demographics, vaccination status, and recent known exposure to COVID-19. RESULTS: Among 3,901 cases and 27,813 date-matched controls, there was a significant interaction between mask use and time period (P < .001). Prior to July 2021, the odds of a reported infection were 66% higher (aOR = 1.66, 95% CI = 1.43-1.91) among participants reporting ≥1 day not wearing a mask compared to those who reported no days (1,592 cases, 11,717 controls). During the Delta-predominant period, the results were similar (aOR = 1.53, 95% CI = 1.23-1.89; 659 cases, 4,649 controls). This association was attenuated during the Omicron-predominant period, where odds of an infection was 16% higher (aOR = 1.16, 95% CI = 1.03-1.32; 1,563 cases, 10,960 controls). CONCLUSIONS: While the effect of not wearing a mask remains significant, during the Omicron-predominant period we observed a decrease in the association between self-reported mask wearing and risk of SARS-CoV-2 infection.

The 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) score and diabetes risk in the Diabetes Prevention Program Outcomes Study (DPPOS).

BACKGROUND: The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) 3rd expert report highlights up-to-date Cancer Prevention Recommendations that may reduce burdens of many chronic diseases, including diabetes. This study examined if following a lifestyle that aligns with the recommendations - assessed via the 2018 WCRF/AICR Score - was associated with lower risk of type 2 diabetes in high-risk adults participating in the Diabetes Prevention Program Outcomes Study (DPPOS). METHODS: The Diabetes Prevention Program (DPP) randomized adults at high risk for diabetes to receive a lifestyle intervention (ILS), metformin (MET) or a placebo (PLB) (mean: 3.2 years), with additional follow-up in DPPOS for 11 years (mean: 15 years total). 2018 WCRF/AICR Scores included seven components: body weight, physical activity, plant-based foods, fast foods, red and processed meat, sugar-sweetened beverages, and alcohol; the optional breastfeeding component was excluded. Scores ranged 0-7 points (with greater scores indicating greater alignment with the recommendations) and were estimated at years 0, 1, 5, 6, 9, and 15 (N=3,147). Fasting glucose and HbA1c were measured every six months and oral glucose tolerance tests were performed annually. Adjusted Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were used to examine the association of both Score changes from years 0-1 and time-dependent Score changes on diabetes risk through DPP and year 15. RESULTS: Scores improved within all groups over 15 years (p<0.001); ILS Scores improved more than MET or PLB Scores after 1 year (p<0.001). For every 1-unit improvement from years 0-1, there was a 31% and 15% lower diabetes risk in ILS (95% CI: 0.56-0.84) and PLB (95% CI: 0.72-0.97) through DPP, and no significant association in MET. Associations were greatest among American Indian participants, followed by non-Hispanic White and Hispanic participants. Score changes from years 0-1 and time-dependent Score changes in ILS and PLB remained associated with lower risk through year 15. CONCLUSIONS: Score improvements were associated with long-term, lower diabetes risk among high-risk adults randomized to ILS and PLB, but not MET. Future research should explore impact of the Score on cancer risk. TRIAL REGISTRATION: Diabetes Prevention Program: NCT00004992 ; Diabetes Prevention Program Outcomes Study: NCT00038727.

Vaccine-induced seroconversion in participants in the North Carolina COVID-19 community Research Partnership.

Well-regulated clinical trials have shown FDA-approved COVID-19 vaccines to be immunogenic and highly efficacious. We evaluated seroconversion rates in adults reporting ≥ 1 dose of an mRNA COVID-19 vaccine in a cohort study of nearly 8000 adults residing in North Carolina to validate immunogenicity using a novel approach: at-home, participant administered point-of-care testing. Overall, 91.4% had documented seroconversion within 75 days of first vaccination (median: 31 days). Participants who were older and male participants were less likely to seroconvert (adults aged 41-65: adjusted hazard ratio [aHR] 0.69 [95% confidence interval (CI): 0.64, 0.73], adults aged 66-95: aHR 0.55 [95% CI: 0.50, 0.60], compared to those 18-40; males: aHR 0.92 [95% CI: 0.87, 0.98], compared to females). Participants with evidence of prior infection were more likely to seroconvert than those without (aHR 1.50 [95% CI: 1.19, 1.88]) and those receiving BNT162b2 were less likely to seroconvert compared to those receiving mRNA-1273 (aHR 0.84 [95% CI: 0.79, 0.90]). Reporting at least one new symptom after first vaccination did not affect time to seroconversion, but participants reporting at least one new symptom after second vaccination were more likely to seroconvert (aHR 1.11 [95% CI: 1.05, 1.17]). This data demonstrates the high community-level immunogenicity of COVID-19 vaccines, albeit with notable differences in older adults, and feasibility of using at-home, participant administered point-of-care testing for community cohort monitoring. Trial registration: ClinicalTrials.gov NCT04342884.

Self-Reported SARS-CoV-2 Vaccination Is Consistent with Electronic Health Record Data among the COVID-19 Community Research Partnership.

Introduction: Observational studies of SARS-CoV-2 vaccine effectiveness depend on accurate ascertainment of vaccination receipt, date, and product type. Self-reported vaccine data may be more readily available to and less expensive for researchers than assessing medical records. Methods: We surveyed adult participants in the COVID-19 Community Research Partnership who had an authenticated Electronic Health Record (EHR) (N = 41,484) concerning receipt of SARS-CoV-2 vaccination using a daily survey beginning in December 2020 and a supplemental survey in September-October 2021. We compared self-reported information to that available in the EHR for the following data points: vaccine brand, date of first dose, and number of doses using rates of agreement and Bland-Altman plots for visual assessment. Self-reported data was available immediately following vaccination (in the daily survey) and at a delayed interval (in a secondary supplemental survey). Results: For the date of first vaccine dose, self-reported "immediate" recall was within ±7 days of the date reported in the "delayed" survey for 87.9% of participants. Among the 19.6% of participants with evidence of vaccination in their EHR, 95% self-reported vaccination in one of the two surveys. Self-reported dates were within ±7 days of documented EHR vaccination for 97.6% of the "immediate" surveys and 92.0% of the "delayed" surveys. Self-reported vaccine product details matched those in the EHR for over 98% of participants for both "immediate" and "delayed" surveys. Conclusions: Self-reported dates and product details for COVID-19 vaccination can be a good surrogate when medical records are unavailable in large observational studies. A secondary confirmation of dates for a subset of participants with EHR data will provide internal validity.

Self-reported mask use among persons with or without SARS CoV-2 vaccination -United States, December 2020-August 2021.

Wearing a facemask can help to decrease the transmission of COVID-19. We investigated self-reported mask use among subjects aged 18 years and older participating in the COVID-19 Community Research Partnership (CRP), a prospective longitudinal COVID-19 surveillance study in the mid-Atlantic and southeastern United States. We included those participants who completed ≥5 daily surveys each month from December 1, 2020 through August 31, 2021. Mask use was defined as self-reported use of a face mask or face covering on every interaction with others outside the household within a distance of less than 6 feet. Participants were considered vaccinated if they reported receiving ≥1 COVID-19 vaccine dose. Participants (n = 17,522) were 91% non-Hispanic White, 68% female, median age 57 years, 26% healthcare workers, with 95% self-reported receiving ≥1 COVID-19 vaccine dose through August 2021; mean daily survey response was 85%. Mask use was higher among vaccinated than unvaccinated participants across the study period, regardless of the month of the first dose. Mask use remained relatively stable from December 2020 through April (range 71-80% unvaccinated; 86-93% vaccinated) and declined in both groups beginning in mid-May 2021 to 34% and 42% respectively in June 2021; mask use increased again since July 2021. Mask use by all was lower during weekends and on Christmas and Easter, regardless of vaccination status. Independent predictors of higher mask use were vaccination, age ≥65 years, female sex, racial or ethnic minority group, and healthcare worker occupation, whereas a history of self-reported prior COVID-19 illness was associated with lower use.

Comparison of ETDRS 7-Field to 4-Widefield Digital Imaging in the Evaluation of Diabetic Retinopathy Severity.

Purpose: To compare Early Treatment Diabetic Retinopathy Study (ETDRS) severity levels between two digital fundus imaging protocols for research studies of diabetic retinopathy: the gold standard 7-field (7F) imaging and the more recent 4-widefield (4W) imaging. Methods: Two hundred twenty-two participants enrolled in the Diabetes Prevention Program Outcomes Study underwent concurrent 7F and 4W imaging. The ETDRS levels from 220 paired gradable images were determined by masked graders. Each image was graded by two independent graders with adjudication by a senior grader, if necessary. Percent agreement between graders and between imaging protocols was evaluated with kappa statistics and weighted kappa statistics. Results: Of 220 gradable eyes, diabetic retinopathy was seen in 11.8%; this was mild in 10.4% and more than mild in 1.4% using 7F imaging. The ETDRS levels showed exact agreement of 95% between 7F and 4W imaging (weighted kappa 0.86). Intergrader agreement for each modality had exact agreement of 89% (weighted kappa of 0.73) for 7F and 91% (weighted kappa 0.77) for 4W. Conclusions: There is substantial agreement in the ETDRS severity level between the 7F and 4W digital imaging protocols, demonstrating that the two imaging protocols are interchangeable. Both 4W and 7F digital imaging protocols can be used for assessing ETDRS levels, even in populations with minimal diabetic retinopathy. Translational Relevance: The 4W protocol requires fewer images than the 7F, is more comfortable for the patients, is easier for photographic capture, and provides diabetic retinopathy data that is equivalent to the 7F imaging protocol.

Islet Autoimmunity in Adults With Impaired Glucose Tolerance and Recently Diagnosed, Treatment Naïve Type 2 Diabetes in the Restoring Insulin SEcretion (RISE) Study.

The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe ß-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing ß-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with ß-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and ß-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose (p = 0.004), and 2 h glucose (p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(-) NdxT2D. T(+) IGT participants demonstrated lower but not significant (p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(-) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide (p = 0.002) compared to T(-), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep (p = 0.010) compared to T(-) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg (p = 0.001) compared to T(-) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and ß-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.

Precision and accuracy of hyperglycemic clamps in a multicenter study.

Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Two-stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. The RISE approach produced high overall precision (3%-9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD < 10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs. adult, IGT vs. diabetes status) and differences in physiology induced by study treatments. The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers.NEW & NOTEWORTHY The Restoring Insulin Secretion (RISE) study centers undertook hyperglycemic clamps using a simplified methodology and a decision guidance algorithm implemented in an easy-to-use spreadsheet. This approach, combined with active management including ongoing central data surveillance and routine feedback to study centers, produced technically excellent standardization of achieved glucose concentrations on repeat studies within and across study centers.

Obstructive Sleep Apnea, Glucose Tolerance, and ß-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet ß-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with ß-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. RESEARCH DESIGN AND METHODS: Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models. RESULTS: Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or ß-cell responses. CONCLUSIONS: In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or ß-cell responses.

OGTT Glucose Response Curves, Insulin Sensitivity, and ß-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve ß-Cell Function.

OBJECTIVE: We examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and ß-cell function (ßCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes.RESEARCH DESIGN AND METHODSThis was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp-measured IS and ßCF at baseline and the change in glucose response curves 12 months after randomization were assessed.RESULTSAt randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (P < 0.05). ßCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher ßCF in BPh and MPh (P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect.CONCLUSIONSDespite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical ß-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of ß-cell dysfunction in youth with this least favorable glucose response curve.

Diet quality, weight loss, and diabetes incidence in the Diabetes Prevention Program (DPP).

BACKGROUND: We evaluated whether diet quality is a predictor of weight loss and reduced diabetes risk, independent of caloric intake in the Diabetes Prevention Program (DPP) cohort, a randomized clinical trial of adults at risk for diabetes. METHODS: This secondary analysis included 2914 participants with available data (964 intensive lifestyle (ILS), 977 metformin, 973 placebo). Dietary intake was assessed using a 117-item food frequency questionnaire. Diet quality was quantified using the Alternative Healthy Eating Index 2010 (AHEI). AHEI ranges from 0 to 110, with higher scores corresponding to higher quality diets. ILS participants had greater improvement (p < 0.001) in AHEI over 1-year (4.2 ± 9.0) compared to metformin (1.2 ± 8.5) and placebo (1.4 ± 8.4). We examined the association between AHEI change and weight change from baseline to 1-year using linear regression, and that between 1-year AHEI change and incident diabetes, using hazard models over an average 3 years follow-up. Models were evaluated within treatment group and adjusted for relevant characteristics including caloric intake, physical activity, BMI and AHEI. Models testing incident diabetes were further adjusted for baseline fasting and 2 h glucose. RESULTS: An increase in AHEI score was associated with weight loss in ILS [ß per 10-point increase (SE) -1.2 kg (0.3, p < 0.001)], metformin [- 0. 90 kg (0.2, p < 0.001)] and placebo [- 0.55 kg (0.2, p = 0.01)]. However, AHEI change was not associated with incident diabetes in any group before or after adjustment for weight change. CONCLUSIONS: Controlling for weight, diet quality was not associated with diabetes incidence but helps achieve weight loss, an important factor in diabetes prevention.

The association of sleep disturbances with glycemia and obesity in youth at risk for or with recently diagnosed type 2 diabetes.

OBJECTIVE: Poor sleep may increase obesity and type 2 diabetes (T2D) risk in youth. We explored whether subjective sleep duration, sleep quality, or risk for obstructive sleep apnea (OSA) are associated with glycemia, body mass index (BMI), or blood pressure (BP) in overweight/obese youth. METHODS: Two-hundred and fourteen overweight/obese youth of 10 to 19 years of age at risk for or recently diagnosed with T2D who were screened for the Restoring Insulin Secretion (RISE) Study had a 2-hour oral glucose tolerance test (OGTT) and completed a Cleveland Adolescent Sleepiness questionnaire and a Sleep Disturbances Scale questionnaire. Independent associations between sleep variables and measures of glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 67% female, 14.1 ± 2.1 years, and BMI 35.9 ± 6.5 kg/m2 . Habitual sleep duration <8 hours was reported in 74%. Daytime sleepiness was reported in 51%, poor sleep quality in 26%, and 30% had high obstructive sleep apnea (OSA) risk. Daytime sleepiness was associated with higher HbA1c (0.2%, P = .02) and 2-hour glucose (13.6 mg/dL, P < .05). Sleep duration, sleep quality, and OSA risk were not associated with the evaluated outcomes. Poor sleep quality and OSA risk were associated with higher BMI (2.9 kg/m2 , P = .004 and 2.83 kg/m2 , P < .003, respectively). CONCLUSIONS: In overweight/obese youth with or at risk for T2D, daytime sleepiness was associated with higher HbA1c. In addition, poor sleep quality and OSA risk were associated with higher BMI. These findings support intervention studies aimed at improving sleep quality in obese youth.

Association of Habitual Daily Physical Activity With Glucose Tolerance and ß-Cell Function in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes From the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: We examined the relationship between habitual daily physical activity and measures of glucose tolerance, insulin sensitivity, and ß-cell responses in adults with impaired glucose tolerance (IGT) or drug-naive, recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants included 230 adults (mean ± SD age 54.5 ± 8.5 years, BMI 35 ± 5.5 kg/m2; 42.6% women) who underwent a 3-h oral glucose tolerance test (OGTT) and hyperglycemic clamp. Wrist accelerometers worn for 7 consecutive days measured total physical activity counts (TAC) (daily mean 233,460 [∼50th percentile for age]). We evaluated whether TAC was associated with fasting plasma glucose, OGTT 2-h plasma glucose or glucose incremental area under the curve (G-iAUC), hyperglycemic clamp measures of insulin sensitivity (steady-state glucose infusion rate/insulin [M/I]) and ß-cell responses (acute C-peptide response to glucose, steady-state C-peptide, and maximal ß-cell response), and OGTT C-peptide index (ΔC-peptide0-30/Δglucose0-30). RESULTS: After adjustments for confounders, there was no association of TAC with fasting plasma glucose, 2-h glucose, or G-iAUC. Higher TAC was associated with higher insulin sensitivity (M/I). After adjusting for M/I, higher TAC was not associated with measures of ß-cell response. CONCLUSIONS: In adults with IGT or drug-naive, recently diagnosed type 2 diabetes, higher levels of habitual physical activity are associated with higher insulin sensitivity. Further studies are needed to understand why higher levels of physical activity are not associated with better ß-cell response.

Association of Self-Reported Sleep and Circadian Measures With Glycemia in Adults With Prediabetes or Recently Diagnosed Untreated Type 2 Diabetes.

OBJECTIVE: Sleep disturbances and circadian misalignment (social jet lag, late chronotype, or shift work) have been associated with worse glycemic control in type 2 diabetes (T2D). Whether these findings apply to adults with prediabetes is yet unexplored. We hypothesized that self-reported short sleep, poor sleep quality, and/or circadian misalignment are associated with higher glycemia, BMI, and blood pressure (BP) in adults with prediabetes or recently diagnosed, untreated T2D. RESEARCH DESIGN AND METHODS: Our cohort included 962 overweight/obese adults ages 20-65 years with prediabetes or recently diagnosed, untreated T2D who completed a 2-h oral glucose tolerance test and validated sleep questionnaires. Independent associations of sleep and circadian variables with glycemia, BMI, and BP were evaluated with regression models. RESULTS: The multiethnic cohort was 55% men, with mean ± SD age 52.2 ± 9.5 years and BMI 34.7 ± 5.5 kg/m2. Mean sleep duration was 6.6 ± 1.3 h. Poor sleep quality was reported by 54% and high risk for obstructive sleep apnea by 64%. HbA1c was significantly higher in those reporting <5 or >8 h sleep per night. Sleep duration >8 h was also associated with higher fasting glucose and <6 h with higher BMI. Shift work was also associated with higher BMI. Social jet lag and delayed chronotype were associated with higher BP. CONCLUSIONS: In our cohort, self-reported short and long sleep were both associated with adverse measures of glycemia, and short sleep and shift work were associated with higher BMI. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia in adults with prediabetes or T2D.