OBJECTIVE To evaluate participant characteristics and long-term changes in glycated hemoglobin (HbA_1c) levels in patients treated with dulaglutide 1.5 mg in a post hoc analysis of the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. RESEARCH DESIGN AND METHODS Change from baseline in HbA_1c was assessed during and up to 72 months of treatment before and after adjustment for duration of diabetes, prior microvascular disease (nephropathy or retinopathy), and BMI. Slope analyses were used to assess the change in HbA_1c during 0–12 months and 12–72 months of therapy. RESULTS HbA_1c was significantly reduced in patients treated with dulaglutide compared with placebo during 72 months of treatment (least-squares mean difference = −0.61%, P < 0.001), regardless of diabetes duration, prior microvascular disease, and BMI (all interaction P > 0.07). Significant reductions were apparent at all time points and were independent of these baseline characteristics. Slope analyses revealed that the dulaglutide group experienced a higher rate of HbA_1c reduction compared with the placebo group from 0 to 12 months before and after adjustment. The dulaglutide group also experienced a higher rate of HbA_1c increase from 12 to 72 months compared with the placebo group that became nonsignificant after adjustment for diabetes duration, prior microvascular disease, and BMI combined. Despite the greater rate of HbA_1c increase in the dulaglutide group during this period, mean HbA_1c values remained below baseline in the dulaglutide group and below mean HbA_1c values in the placebo group. CONCLUSIONS Dulaglutide 1.5-mg treatment was statistically associated with a long-lasting decrease in HbA_1c over 72 months, irrespective of baseline duration of diabetes, microvascular disease, and BMI.

OBJECTIVE The primary aim was to assess associations between total steps per day and incident diabetes, whereas the secondary aim was to assess whether the intensity and/or cadence of steps is associated with incident diabetes. RESEARCH DESIGN AND METHODS Women without physician-diagnosed diabetes (n = 4,838; mean [SD] age 78.9 [6.7] years) were followed up to 6.9 years; 395 developed diabetes. Hip-worn ActiGraph GT3X+ accelerometers worn for 1 week enabled measures of total, light-intensity, and moderate- to vigorous-intensity (MV-intensity) steps per day. Using Cox proportional hazards analysis we modeled adjusted change in the hazard rate for incident diabetes associated with total, light-intensity, and MV-intensity steps per day. We further estimated the proportion of the steps-diabetes association mediated by BMI. RESULTS On average, participants took 3,729 (SD 2,114) steps/day, of which 1,875 (791) were light-intensity steps and 1,854 ± 1,762 were MV-intensity. More steps per day were associated with a lower hazard rate for incident diabetes. Confounder-adjusted models for a 2,000 steps/day increment yielded hazard ratio (HR) 0.88 (95% CI 0.78–1.00; P = 0.046). After further adjustment for BMI, HR was 0.90 (95% CI 0.80–1.02; P = 0.11). BMI did not significantly mediate the steps-diabetes association (proportion mediated = 17.7% [95% CI −55.0 to 142.0]; P = 0.09]). The relationship between MV-intensity steps per day (HR 0.86 [95% CI 0.74–1.00]; P = 0.04) and incident diabetes was stronger than for light-intensity steps per day (HR 0.97 [95% CI 0.73–1.29]; P = 0.84). CONCLUSIONS These findings suggest that for older adults, more steps per day are associated with lower incident diabetes and MV-intensity steps are most strongly associated with a lower hazard of diabetes. This evidence supports that regular stepping is an important risk factor for type 2 diabetes prevention in older adults.

OBJECTIVE To evaluate the association of a healthy lifestyle, involving seven low-risk factors mentioned in diabetes management guidelines (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, less sedentary behavior, adequate sleep duration, and appropriate social connection), with all-cause and cause-specific mortality among individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS This study included 13,366 participants with baseline type 2 diabetes from the UK Biobank free of cardiovascular disease (CVD) and cancer. Lifestyle information was collected through a baseline questionnaire. RESULTS During a median follow-up of 11.7 years, 1,561 deaths were documented, with 625 from cancer, 370 from CVD, 115 from respiratory disease, 81 from digestive disease, and 74 from neurodegenerative disease. In multivariate-adjusted model, each lifestyle factor was significantly associated with all-cause mortality, and hazard ratios associated with the lifestyle score (scoring 6–7 vs. 0–2 unless specified) were 0.42 (95% CI 0.34, 0.52) for all-cause mortality, 0.57 (0.41, 0.80) for cancer mortality, 0.35 (0.22, 0.56) for CVD mortality, 0.26 (0.10, 0.63) for respiratory mortality, and 0.28 (0.14, 0.53) for digestive mortality (scoring 5–7 vs. 0–2). In the population-attributable risk analysis, 29.4% (95% CI 17.9%, 40.9%) of deaths were attributable to a poor lifestyle (scoring 0–5). The association between a healthy lifestyle and all-cause mortality was consistent, irrespective of factors reflecting diabetes severity (diabetes duration, glycemic control, diabetes-related microvascular disease, and diabetes medication). CONCLUSIONS A healthy lifestyle was associated with a lower risk of all-cause mortality and mortality due to CVD, cancer, respiratory disease, and digestive disease among individuals with type 2 diabetes.

OBJECTIVE Insulin response is related to overall health. Diet modulates insulin response. We investigated whether insulinemic potential of diet is associated with risk of all-cause and cause-specific mortality. RESEARCH DESIGN AND METHODS We prospectively followed 63,464 women from the Nurses’ Health Study (1986–2016) and 42,880 men from the Health Professionals Follow-up Study (1986–2016). Diet was assessed by food frequency questionnaires every 4 years. The insulinemic potential of diet was evaluated using a food-based empirical dietary index for hyperinsulinemia (EDIH), which was predefined based on predicting circulating C-peptide concentrations. RESULTS During 2,792,550 person-years of follow-up, 38,329 deaths occurred. In the pooled multivariable-adjusted analyses, a higher dietary insulinemic potential was associated with an increased risk of mortality from all-cause (hazard ratio [HR] comparing extreme quintiles: 1.33; 95% CI 1.29, 1.38; P-trend <0.001), cardiovascular disease (CVD) (HR 1.37; 95% CI 1.27, 1.46; P-trend <0.001), and cancers (HR 1.20; 95% CI 1.13, 1.28; P-trend <0.001). These associations were independent of BMI and remained significant after further adjustment for other well-known dietary indices. Furthermore, compared with participants whose EDIH scores were stable over an 8-year period, those with the greatest increases had a higher subsequent risk of all-cause (HR 1.13; 95% CI 1.09, 1.18; P-trend <0.001) and CVD (HR 1.10; 95% CI 1.01, 1.21; P-trend = 0.006) mortality. CONCLUSIONS Higher insulinemic potential of diet was associated with increased risk of all-cause, CVD, and cancer mortality. Adopting a diet with low insulinemic potential might be an effective approach to improve overall health and prevent premature death.

OBJECTIVE LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

OBJECTIVE Irregular menstrual cycles are associated with increased cardiovascular mortality. Polycystic ovary syndrome (PCOS) is characterized by androgen excess and irregular menses; androgens are drivers of increased metabolic risk in women with PCOS. Combined oral contraceptive pills (COCPs) are used in PCOS both for cycle regulation and to reduce the biologically active androgen fraction. We examined COCP use and risk of dysglycemia (prediabetes and type 2 diabetes) in women with PCOS. RESEARCH DESIGN AND METHODS Using a large U.K. primary care database (The Health Improvement Network [THIN]; 3.7 million patients from 787 practices), we carried out a retrospective population-based cohort study to determine dysglycemia risk (64,051 women with PCOS and 123,545 matched control subjects), as well as a nested pharmacoepidemiological case-control study to investigate COCP use in relation to dysglycemia risk (2,407 women with PCOS with [case subjects] and without [control subjects] a diagnosis of dysglycemia during follow-up). Cox models were used to estimate the unadjusted and adjusted hazard ratio, and conditional logistic regression was used to obtain adjusted odds ratios (aORs). RESULTS The adjusted hazard ratio for dysglycemia in women with PCOS was 1.87 (95% CI 1.78–1.97, P < 0.001; adjustment for age, social deprivation, BMI, ethnicity, and smoking), with increased rates of dysglycemia in all BMI subgroups. Women with PCOS and COCP use had a reduced dysglycemia risk (aOR 0.72, 95% CI 0.59–0.87). CONCLUSIONS In this study, limited by its retrospective nature and the use of routinely collected electronic general practice record data, which does not allow for exclusion of the impact of prescription-by-indication bias, women with PCOS exposed to COCPs had a reduced risk of dysglycemia across all BMI subgroups. Future prospective studies should be considered for further understanding of these observations and potential causality.

OBJECTIVE To explore the potential relevance of muscle mass as a variable contributor to BMI in limitations on BMI-based predictions of diabetes remission (DR) after Roux-en-Y gastric bypass (RYGB). RESEARCH DESIGN AND METHODS We evaluated the relationship between muscle mass and BMI in 501 patients with type 2 diabetes mellitus and overweight or obesity, of whom 186 patients who underwent RYGB were studied for determination of the role of baseline muscle mass and BMI in predicting DR. Muscle mass was assessed by estimated fat-free mass index (eFFMI) and psoas cross-sectional area (CSA). RESULTS A nonlinear relationship existed between psoas CSA and BMI, whereas psoas CSA showed a highly positive correlation with eFFMI. Baseline psoas CSA and eFFMI were better than BMI for predicting 1- and 5-year DR. CONCLUSIONS The nonlinear relationship between muscle mass and BMI may partially contribute to BMI limitations in predicting DR after RYGB.

OBJECTIVE Posttransplantation diabetes mellitus (PTDM) effects up to 30% of all kidney transplant recipients (KTR). Recent studies in mice found that sufficient androgen levels are necessary for β-cell health and adequate insulin secretion. This raises the question whether a similar relationship might be present in KTR. Hence, we hypothesized that dihydrotestosterone and testosterone are associated with the development of PTDM in male KTR. RESEARCH DESIGN AND METHODS We conducted a post hoc analyses of a prospective single-center cohort study including adult male KTR with a functioning graft ≥1 year posttransplantation. Androgen levels were assessed by liquid chromatography–tandem mass spectrometry. Development of PTDM was defined according to the American Diabetes Association’s criteria. RESULTS We included 243 male KTR (aged 51 ± 14 years), with a median dihydrotestosterone 0.9 (0.7–1.3) nmol/L and testosterone of 12.1 (9.4–15.8) nmol/L. During 5.3 (3.7–5.8) years of follow-up, 28 KTR (11.5%) developed PTDM. A clear association was observed, as 15 (19%), 10 (12%), and 3 (4%) male KTR developed PTDM in the respective tertiles of dihydrotestosterone (P = 0.008). In Cox regression analyses, both dihydrotestosterone and testosterone as continuous variables were inversely associated with the risk to development PTDM, independent of glucose and HbA_1c (hazard ratio [HR] 0.31 [95% CI 0.16–0.59], P < 0.001; and HR 0.32 [95% CI 0.15–0.68], P = 0.003, respectively). CONCLUSIONS Our results suggest that low androgen levels are a novel potential modifiable risk factor for the development of PTDM in male KTR.

OBJECTIVE To examine the ethnic differences in insulin sensitivity (S_I) as measured by the minimal model approach (S_I-MM) and the reference method, the euglycemic-hyperinsulinemic clamp (EHC). RESEARCH DESIGN AND METHODS In a prospective study design, thirty Black Americans (BA) were age, sex, and BMI matched with non-Hispanic Whites (NHW). Participants underwent frequently sampled intravenous tolerance test (FSIVGTT) and EHC on 2 separate days during a single visit. RESULTS S_I-MM values were significantly lower in BA when compared with NHW (0.035 ± 0.025 vs. 0.058 ± 0.036 [dL/min]/[μU/mL]; P = 0.003). However, there were no ethnic differences in S_I measured by EHC (0.028 ± 0.012 vs. 0.035 ± 0.019 [dL/min]/[μU/mL]; P = 0.18). CONCLUSIONS S_I-MM systematically underestimates S_I in BA when compared with NHW. These findings suggest that studies inferring lower S_I in BA based on FSIVGTT and S_I-MM should be interpreted cautiously.

OBJECTIVE We aimed to test whether type 2 diabetes (T2D)–associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. RESULTS None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/I_F]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/I_F), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. CONCLUSIONS In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.

OBJECTIVE Stress, sleep, eating behavior, and physical activity are associated with weight change and insulin resistance (IR). The aim of this analysis was the assessment of the overall and sex-specific associations of psychobehavioral variables throughout the 3-year PREVIEW intervention using the homeostatic model assessment of IR (HOMA-IR), BMI, and length of time in the study. RESEARCH DESIGN AND METHODS Associations of psychobehavioral variables, including stress, mood, eating behavior, physical activity (PA), and sleep, with BMI, HOMA-IR, and time spent in the study were assessed in 2,184 participants with prediabetes and overweight/obesity (n = 706 men; n = 1,478 women) during a 3-year lifestyle intervention using linear mixed modeling and general linear modeling. The study was a randomized multicenter trial using a 2 × 2 diet-by-PA design. RESULTS Overall, cognitive restraint and PA increased during the intervention compared with baseline, whereas BMI, HOMA-IR, disinhibition, hunger, and sleepiness decreased (all P < 0.05). Cognitive restraint and PA were negatively, whereas disinhibition, hunger, stress, and total mood disturbance were positively, associated with both BMI and HOMA-IR. Sleep duration, low sleep quality, total mood disturbance, disinhibition, and hunger scores were positively associated with HOMA-IR for men only. Participants who dropped out at 6 months had higher stress and total mood disturbance scores at baseline and throughout their time spent in the study compared with study completers. CONCLUSIONS Eating behavior and PA, control of stress, mood disturbance, and sleep characteristics were associated with BMI, HOMA-IR, and time spent in the study, with different effects in men and women during the PREVIEW lifestyle intervention study.

OBJECTIVE The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. RESEARCH DESIGN AND METHODS We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity. RESULTS Higher weighted GRS was associated with lower oral disposition index (β = −0.11; 95% CI −0.19, −0.02) and insulinogenic index (β = −0.08; 95% CI −0.17, −0.001), but not with fasting glucose (β = 0.01; 95% CI −0.01, 0.02), 2-h glucose (β = 0.03; 95% CI −0.0004, 0.06), or HOMA-IR (β = 0.02; 95% CI −0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. CONCLUSIONS Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.

OBJECTIVE To examine changes in and the relationships between diabetes management and rural and urban residence. RESEARCH DESIGN AND METHODS Using National Health and Nutrition Examination Survey (1999–2018) data from 6,372 adults aged ≥18 years with self-reported diagnosed diabetes, we examined poor ABCS: A 1C >9% (>75 mmol/mol), B lood pressure (BP) ≥140/90 mmHg, C holesterol (non-HDL) ≥160 mg/dL (≥4.1 mmol/L), and current S moking. We compared odds of urban versus rural residents (census tract population size ≥2,500 considered urban, otherwise rural) having poor ABCS across time (1999–2006, 2007–2012, and 2013–2018), overall and by sociodemographic and clinical characteristics. RESULTS During 1999–2018, the proportion of U.S. adults with diabetes residing in rural areas ranged between 15% and 19.5%. In 1999–2006, there were no statistically significant rural-urban differences in poor ABCS. However, from 1999–2006 to 2013–2018, there were greater improvements for urban adults with diabetes than for rural for BP ≥140/90 mmHg (relative odds ratio [OR] 0.8, 95% CI 0.6–0.9) and non-HDL ≥160 mg/dL (≥4.1 mmol/L) (relative OR 0.45, 0.4–0.5). These differences remained statistically significant after adjustment for race/ethnicity, education, poverty levels, and clinical characteristics. Yet, over the 1999–2018 time period, minority race/ethnicity, lower education attainment, poverty, and lack of health insurance coverage were factors associated with poorer A, B, C, or S in urban adults compared with their rural counterparts. CONCLUSIONS Over two decades, rural U.S. adults with diabetes have had less improvement in BP and cholesterol control. In addition, rural-urban differences exist across sociodemographic groups, suggesting that efforts to narrow this divide may need to address both socioeconomic and clinical aspects of care.

OBJECTIVE Obesity, which is associated with nonalcoholic fatty liver (NAFL), has increased among people with type 1 diabetes. Therefore, we explored the associations between body fat distribution and NAFL in this population. RESEARCH DESIGN AND METHODS This study included 121 adults with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study for whom NAFL was determined by magnetic resonance imaging. Body composition was assessed by dual-energy X-ray absorptiometry. Genetic data concerning PNPLA3 rs738409 and TM6SF2 rs58542926 were available as a directly genotyped polymorphism. Associations between body fat distribution, waist-to-height ratio (WHtR), BMI, and NAFL were explored using logistic regression. A receiver operating characteristic (ROC) curve was used to determine the WHtR and BMI thresholds with the highest sensitivity and specificity to detect NAFL. RESULTS Median age was 38.5 (33–43.7) years, duration of diabetes was 21.2 (17.9–28.4) years, 52.1% were women, and the prevalence of NAFL was 11.6%. After adjusting for sex, age, duration of diabetes, and PNPLA3 rs738409, the volume (P = 0.03) and percentage (P = 0.02) of visceral adipose tissue were associated with NAFL, whereas gynoid, appendicular, and total adipose tissues were not. The area under the curve between WHtR and NAFL was larger than BMI and NAFL (P = 0.04). The WHtR cutoff of 0.5 showed the highest sensitivity (86%) and specificity (55%), whereas the BMI of 26.6 kg/m² showed 79% sensitivity and 57% specificity. CONCLUSIONS Visceral adipose tissue is associated with NAFL in adults with type 1 diabetes, and WHtR may be considered when screening for NAFL in this population.

OBJECTIVE Studies have shown a disparate association between body composition and the risk of type 2 diabetes. We assessed whether associations between differences in body composition and type 2 diabetes vary among ethnic groups with disparate cardiometabolic risk. RESEARCH DESIGN AND METHODS We used data from the Healthy Life in an Urban Setting (HELIUS) study, including individuals aged 18–70 years of African Surinamese (n = 3,997), South Asian Surinamese (n = 2,956), Turkish (n = 3,546), Moroccan (n = 3,850), Ghanaian (n = 2,271), and Dutch (n = 4,452) origin living in Amsterdam. Type 2 diabetes was defined using the World Health Organization criteria. Logistic regression was used to assess the relation between body composition and type 2 diabetes. Waist-to-hip ratio (WHR), waist circumference, BMI, and body fat percentage by bioelectrical impedance were used to estimate body composition. RESULTS Per unit change in BMI, only Ghanaian (odds ratio [OR] 0.94 [95% CI 0.89–0.99]) and Moroccan (0.94 [0.89–0.99]) women had a smaller increase in type 2 diabetes compared with the Dutch population, whereas the ORs for body fat percentage were 0.94 (0.89–1.00) for Ghanaian, 0.93 (0.88–0.99) for Moroccan, and 0.95 (0.90–1.00) for South Asian Surinamese women. There was no interaction between WHR and ethnicity on the risk of type 2 diabetes, and there were no differences in men. WHR had the highest precision in predicting type 2 diabetes in both men (C statistic = 0.78) and women (C statistic = 0.81). CONCLUSIONS The association between differences in body composition and type 2 diabetes is roughly the same in all ethnic groups. WHR seems the most reliable and consistent predictor of type 2 diabetes regardless of ethnic background.

OBJECTIVE To assess adherence to the three main drug classes in real-world patients with type 2 diabetes using biochemical urine testing, and to determine the association of nonadherence with baseline demographics, treatment targets, and complications. RESEARCH DESIGN AND METHODS Analyses were performed of baseline data on 457 patients in the DIAbetes and LifEstyle Cohort Twente (DIALECT) study. Adherence to oral antidiabetics (OADs), antihypertensives, and statins was determined by analyzing baseline urine samples using liquid chromatography–tandem mass spectrometry. Primary outcomes were microvascular and macrovascular complications and treatment targets of LDL cholesterol, HbA_1c, and blood pressure. These were assessed cross-sectionally at baseline. RESULTS Overall, 89.3% of patients were identified as adherent. Adherence rates to OADs, antihypertensives, and statins were 95.7%, 92.0%, and 95.5%, respectively. The prevalence of microvascular (81.6% vs. 66.2%; P = 0.029) and macrovascular complications (55.1% vs. 37.0%; P = 0.014) was significantly higher in nonadherent patients. The percentage of patients who reached an LDL cholesterol target of ≤2.5 mmol/L was lower (67.4% vs. 81.1%; P = 0.029) in nonadherent patients. Binary logistic regression indicated that higher BMI, current smoking, elevated serum LDL cholesterol, high HbA_1c, presence of diabetic kidney disease, and presence of macrovascular disease were associated with nonadherence. CONCLUSIONS Although medication adherence of real-world type 2 diabetes patients managed in specialist care was relatively high, the prevalence of microvascular and macrovascular complications was significantly higher in nonadherent patients, and treatment targets were reached less frequently. This emphasizes the importance of objective detection and tailored interventions to improve adherence.

OBJECTIVE Obesity is an established risk factor for severe coronavirus disease 2019 (COVID-19), but the contribution of overweight and/or diabetes remains unclear. In a multicenter, international study, we investigated if overweight, obesity, and diabetes were independently associated with COVID-19 severity and whether the BMI-associated risk was increased among those with diabetes. RESEARCH DESIGN AND METHODS We retrospectively extracted data from health care records and regional databases of hospitalized adult patients with COVID-19 from 18 sites in 11 countries. We used standardized definitions and analyses to generate site-specific estimates, modeling the odds of each outcome (supplemental oxygen/noninvasive ventilatory support, invasive mechanical ventilatory support, and in-hospital mortality) by BMI category (reference, overweight, obese), adjusting for age, sex, and prespecified comorbidities. Subgroup analysis was performed on patients with preexisting diabetes. Site-specific estimates were combined in a meta-analysis. RESULTS Among 7,244 patients (65.6% overweight/obese), those with overweight were more likely to require oxygen/noninvasive ventilatory support (random effects adjusted odds ratio [aOR], 1.44; 95% CI 1.15–1.80) and invasive mechanical ventilatory support (aOR, 1.22; 95% CI 1.03–1.46). There was no association between overweight and in-hospital mortality (aOR, 0.88; 95% CI 0.74–1.04). Similar effects were observed in patients with obesity or diabetes. In the subgroup analysis, the aOR for any outcome was not additionally increased in those with diabetes and overweight or obesity. CONCLUSIONS In adults hospitalized with COVID-19, overweight, obesity, and diabetes were associated with increased odds of requiring respiratory support but were not associated with death. In patients with diabetes, the odds of severe COVID-19 were not increased above the BMI-associated risk.

OBJECTIVE Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity. RESEARCH DESIGN AND METHODS Data on mother/offspring pairs (N = 4,832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow-up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes. RESULTS In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, P value) BMI (0.26, 0.12–0.39, <0.001), BMI z-score (0.072, 0.033–0.11, <0.001), fat mass (kg) (0.51, 0.26–0.76, <0.001), percentage of body fat (0.61, 0.27–0.95, <0.001), and sum of skinfolds (mm) (1.14, 0.43–1.86, 0.0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2.5% and 1%, respectively), fat mass (3.1%, 1.2%), percentage of body fat (3.6%, 1.8%), and sum of skinfolds (2.9%, 1.8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22.0% and 21.0%, respectively), percentage of body fat (15.0%, 18.0%), and sum of skinfolds (15.0%, 20.0%). CONCLUSIONS Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity.

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 β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-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 HbA_1c, 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 HbA_1c (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 β-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 HbA_1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.

OBJECTIVE To assess the prevalence of and trends in complications among U.S. adults with newly diagnosed diabetes. RESEARCH DESIGN AND METHODS We included 1,486 nonpregnant adults (aged ≥20 years) with newly diagnosed diabetes (diagnosed within the past 2 years) from the 1988–1994 and 1999–2018 National Health and Nutrition Examination Survey. We estimated trends in albuminuria (albumin-to-creatinine ratio ≥30 mg/g), reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m²), retinopathy (any retinal microaneurysms or blot hemorrhages), and self-reported cardiovascular disease (history of congestive heart failure, heart attack, or stroke). RESULTS From 1988–1994 to 2011–2018, there was a significant decrease in the prevalence of albuminuria (38.9 to 18.7%, P for trend <0.001) but no change in the prevalence of reduced eGFR (7.5 to 9.9%, P for trend = 0.30), retinopathy (1988–1994 to 1999–2008 only; 13.2 to 12.1%, P for trend = 0.86), or self-reported cardiovascular disease (19.0 to 16.5%, P for trend = 0.64). There were improvements in glycemic, blood pressure, and lipid control in the population, and these partially explained the decline in albuminuria. Complications were more common at the time of diabetes diagnosis for adults who were older, lower income, less educated, and obese. CONCLUSIONS Over the past three decades, there have been encouraging reductions in albuminuria and risk factor control in adults with newly diagnosed diabetes. However, the overall burden of complications around the time of the diagnosis remains high.