Continuous subcutaneous insulin infusion (CSII) is the most advanced form of insulin delivery, but it requires structured education to provide users with the necessary knowledge/skills and to support their motivation. Currently, no structured education program designed to provide this training has been evaluated. We developed a CSII-specific, structured education program (Insulin Pump Treatment [INPUT]) and evaluated its impact on glycemic control, behavior, and psychosocial status.

This was a multicenter, randomized, parallel trial with a 6-month follow-up. Eligible participants (age 16–75 years) currently were treated with insulin pump therapy. Participants were randomly assigned (1:1) to the INPUT program or to usual care using a computer-generated algorithm, with study center as the stratification factor. The primary outcome was HbA_1c change from baseline to 6 months. Secondary outcomes were incidence of severe hypoglycemia and changes in behavioral and psychosocial measures.

Between 1 April 2016 and 26 April 2016, 268 people with diabetes and a mean duration of CSII therapy of 9.5 years were randomly assigned to the INPUT group (n = 135) or control group (n = 133). At 6 months, HbA_1c improved in the INPUT group (8.33 ± 0.8 vs. 8.04 ± 0.9; P < 0.0001) but not in the control group (8.33 ± 1.0 vs. 8.27 ± 1.0; P = 0.11). The between-group difference in HbA_1c reduction was significant, favoring INPUT (–0.28% vs. –0.06%, –0.22%, 95% CI –0.38 to –0.06; P = 0.0029). The incidence rate ratio of severe hypoglycemia was 3.55 times higher for participants in the control group than for those in the INPUT group (95% CI 1.50–8.43; P = 0.0041).

The INPUT education program led to a significant improvement in glycemic control and incidence of severe hypoglycemia in insulin pump users.

Comorbid depression is associated with increased health care utilization and cost. We examined the effects of peer support on acute care (AC) and hospital utilization in individuals with diabetes with or without depressive symptoms.

This was a cluster-randomized controlled trial conducted in 2010–2012, with the clusters being practices and their surrounding communities. Adults with type 2 diabetes who wanted help with self-management were eligible to participate. Those without a doctor, with limited life expectancy, with plans to move within the next year, and with an unwillingness to work with a peer advisor were excluded. Intervention participants received 1 year of peer support. Control participants received usual care. The Patient Health Questionnaire (PHQ-8) (range 0–24; 5 indicates mild and 10 indicates moderate depressive symptoms) assessed depressive symptoms. AC and hospital utilization were measured by self-report. Data were collected at baseline, 6 months, and 12 months. Quasi-Poisson regression using generalized estimating equations examined differences in utilization per year attributable to the intervention for those with and without mild depressive symptoms (and separately, moderate depressive symptoms), controlling for imbalance across treatment arms.

At baseline, half of the sample reported mild depressive symptoms (52% intervention and 48% control, P = 0.37), a quarter reported moderate depressive symptoms (25% intervention and 26% control, P = 1.0), and there were no significant differences in utilization. A total of 168 intervention (six clusters) and 187 control (five clusters) participants had follow-up data. In individuals with mild depressive symptoms, the incident rate ratio (IRR) for hospitalization among intervention compared with control was 0.26 (95% CI 0.08–0.84) per 10 patient-years. The IRR for AC was 0.55 (95% CI 0.28–1.07) per 10 person-years. Findings were similar for individuals with moderate depressive symptoms.

Peer support lowered AC visits and hospitalizations for individuals with depressive symptoms but not for those without depressive symptoms; these findings can guide resource allocation for population health management.

To compare glycemic control, quality of life, and pregnancy outcomes of women using insulin pumps and multiple daily injection therapy (MDI) during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT).

This was a prespecified analysis of CONCEPTT involving 248 pregnant women from 31 centers. Randomization was stratified for pump versus MDI and HbA_1c. The primary outcome was change in HbA_1c from randomization to 34 weeks’ gestation. Key secondary outcomes were continuous glucose monitoring (CGM) measures, maternal-infant health, and patient-reported outcomes.

At baseline, pump users were more often in stable relationships (P = 0.003), more likely to take preconception vitamins (P = 0.03), and less likely to smoke (P = 0.02). Pump and MDI users had comparable first-trimester glycemia: HbA_1c 6.84 ± 0.71 vs. 6.95 ± 0.58% (51 ± 7.8 vs. 52 ± 6.3 mmol/mol) (P = 0.31) and CGM time in target (51 ± 14 vs. 50 ± 13%) (P = 0.40). At 34 weeks, MDI users had a greater decrease in HbA_1c (–0.55 ± 0.59 vs. –0.32 ± 0.65%, P = 0.001). At 24 and 34 weeks, MDI users were more likely to achieve target HbA_1c (P = 0.009 and P = 0.001, respectively). Pump users had more hypertensive disorders (P = 0.011), mainly driven by increased gestational hypertension (14.4 vs. 5.2%; P = 0.025), and more neonatal hypoglycemia (31.8 vs. 19.1%, P = 0.05) and neonatal intensive care unit (NICU) admissions >24 h (44.5 vs. 29.6%; P = 0.02). Pump users had a larger reduction in hypoglycemia-related anxiety (P = 0.05) but greater decline in health/well-being (P = 0.02).

In CONCEPTT, MDI users were more likely to have better glycemic outcomes and less likely to have gestational hypertension, neonatal hypoglycemia, and NICU admissions than pump users. These data suggest that implementation of insulin pump therapy is potentially suboptimal during pregnancy.

The type 2 diabetes–associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes.

We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2–45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.

During follow-up (median 5.2 years, range 0.2–12.6), 62% of the single autoantibody–positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody–positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age.

The type 2 diabetes–associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

It is well established that diabetic nephropathy increases the risk of cardiovascular disease (CVD), but how severe diabetic retinopathy (SDR) impacts this risk has yet to be determined.

The cumulative incidence of various CVD events, including coronary heart disease (CHD), peripheral artery disease (PAD), and stroke, retrieved from registries, was evaluated in 1,683 individuals with at least a 30-year duration of type 1 diabetes drawn from the Finnish Diabetic Nephropathy Study (FinnDiane). The individuals were divided into four groups according to the presence of diabetic kidney disease (DKD) and/or SDR (+DKD/+SDR, +DKD/–SDR, –DKD/+SDR, and –DKD/–SDR) at baseline visit. Furthermore, age-specific incidences were compared with 4,016 control subjects without diabetes. SDR was defined as laser photocoagulation and DKD as estimated glomerular filtration rate <60 mL/min/1.73 m².

During 12,872 person-years of follow-up, 416 incident CVD events occurred. Even in the absence of DKD, SDR increased the risk of any CVD (hazard ratio 1.46 [95% CI 1.11–1.92]; P < 0.01), after adjustment for diabetes duration, age at diabetes onset, sex, smoking, blood pressure, waist-to-hip ratio, history of hypoglycemia, and serum lipids. In particular, SDR alone was associated with the risk of PAD (1.90 [1.13–3.17]; P < 0.05) and CHD (1.50 [1.09–2.07; P < 0.05) but not with any stroke. Moreover, DKD increased the CVD risk further (2.85 [2.13–3.81]; P < 0.001). However, the risk was above that of the control subjects without diabetes also in patients without microvascular complications, until the patients reached their seventies.

SDR alone, even without DKD, increases cardiovascular risk, particularly for PAD, independently of common cardiovascular risk factors in long-standing type 1 diabetes. More remains to be done to fully understand the link between SDR and CVD. This knowledge could help combat the enhanced cardiovascular risk beyond currently available regimens.

To evaluate the prevalence of hearing impairment in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and compare with that of a spousal control group without diabetes. Among participants with type 1 diabetes, to evaluate the association of hearing impairment with prior DCCT therapy and overall glycemia.

DCCT/EDIC participants (n = 1,150) and 288 spouses without diabetes were recruited for the DCCT/EDIC Hearing Study. All subjects completed a self-administered questionnaire, medical history, and physical measurements. Audiometry was performed by study-certified personnel; audiograms were assessed centrally. Speech-frequency (pure-tone average [PTA] thresholds at 500, 1,000, 2,000, and 4,000 Hz) and high-frequency impairment (PTA thresholds at 3,000, 4,000, 6,000, and 8,000 Hz) were defined as PTA >25 dB hearing loss. Logistic regression models were adjusted for age and sex.

DCCT/EDIC participants and spousal control subjects were similar in age, race, education, smoking, and systolic blood pressure. There were no statistically significant differences between groups in the prevalence or adjusted odds of speech- or high-frequency impairment in either ear. Among participants with type 1 diabetes, for every 10% increase in the time-weighted mean HbA_1c, there was a 32% (95% CI 1.15–1.50) and 19% (95% CI 1.07–1.33) increase in speech- and high-frequency hearing impairment, respectively.

We found no significant difference in the prevalence of hearing impairment between the group with type 1 diabetes and the spousal control group. Among those with type 1 diabetes, higher mean HbA_1c over time was associated with hearing impairment.

To examine the relative importance of maternal preexisting type 1 diabetes (T1D), preexisting type 2 diabetes (T2D), and gestational diabetes mellitus (GDM) on risk of attention deficit/hyperactivity disorder (ADHD) in offspring.

This retrospective birth cohort study included 333,182 singletons born in 1995–2012 within Kaiser Permanente Southern California hospitals. Children were prospectively followed through electronic medical records from age 4 years. Relative risks of ADHD associated with diabetes exposures in utero were estimated by hazard ratios (HRs) using Cox regression with adjustment for potential confounders. For GDM, timing of exposure was evaluated by gestational age at diagnosis and severity was assessed by the need for antidiabetes medication treatment during pregnancy.

A total of 37,878 (11.4%) children were exposed to diabetes (522 exposed to T1D, 7,822 T2D, and 29,534 GDM). During a median of 4.9 years (interquartile range 2.2, 9.6) of follow-up after age 4 years, 17,415 (5.2%) children were diagnosed with ADHD. ADHD risk was not associated with GDM taken as a whole (P = 0.50) or with gestational age at GDM diagnosis (P = 0.16). However, the risk was significantly greater for the GDM requiring versus not requiring antidiabetes medications (P < 0.001). Compared with children unexposed to diabetes, the adjusted HRs for ADHD in children were 1.57 (95% CI 1.09–2.25) for exposure to T1D, 1.43 (1.29–1.60) for T2D, 1.26 (1.14–1.41) for GDM requiring antidiabetes medications, and 0.93 (0.86–1.01) for GDM not requiring medications.

The hierarchy of risks suggests that severity of maternal diabetes (T1D vs. T2D vs. GDM requiring antidiabetes medications) influences the risk of ADHD in offspring of mothers with diabetes.

The goal of this study was to describe the development and validation of an artificial intelligence–based, deep learning algorithm (DLA) for the detection of referable diabetic retinopathy (DR).

A DLA using a convolutional neural network was developed for automated detection of vision-threatening referable DR (preproliferative DR or worse, diabetic macular edema, or both). The DLA was tested by using a set of 106,244 nonstereoscopic retinal images. A panel of ophthalmologists graded DR severity in retinal photographs included in the development and internal validation data sets (n = 71,043); a reference standard grading was assigned once three graders achieved consistent grading outcomes. For external validation, we tested our DLA using 35,201 images of 14,520 eyes (904 eyes with any DR; 401 eyes with vision-threatening referable DR) from population-based cohorts of Malays, Caucasian Australians, and Indigenous Australians.

Among the 71,043 retinal images in the training and validation data sets, 12,329 showed vision-threatening referable DR. In the internal validation data set, the area under the curve (AUC), sensitivity, and specificity of the DLA for vision-threatening referable DR were 0.989, 97.0%, and 91.4%, respectively. Testing against the independent, multiethnic data set achieved an AUC, sensitivity, and specificity of 0.955, 92.5%, and 98.5%, respectively. Among false-positive cases, 85.6% were due to a misclassification of mild or moderate DR. Undetected intraretinal microvascular abnormalities accounted for 77.3% of all false-negative cases.

This artificial intelligence–based DLA can be used with high accuracy in the detection of vision-threatening referable DR in retinal images. This technology offers potential to increase the efficiency and accessibility of DR screening programs.

This study analyzed whether area deprivation is associated with disparities in health care of pediatric type 1 diabetes in Germany.

We selected patients <20 years of age with type 1 diabetes and German residence documented in the "diabetes patient follow-up" (Diabetes-Patienten-Verlaufsdokumentation [DPV]) registry for 2015/2016. Area deprivation was assessed by quintiles of the German Index of Multiple Deprivation (GIMD 2010) at the district level and was assigned to patients. To investigate associations between GIMD 2010 and indicators of diabetes care, we used multivariable regression models (linear, logistic, and Poisson) adjusting for sex, age, migration background, diabetes duration, and German federal state.

We analyzed data from 29,284 patients. From the least to the most deprived quintile, use of continuous glucose monitoring systems (CGMS) decreased from 6.3 to 3.4% and use of long-acting insulin analogs from 80.8 to 64.3%, whereas use of rapid-acting insulin analogs increased from 74.7 to 79.0%; average HbA_1c increased from 7.84 to 8.07% (62 to 65 mmol/mol), and the prevalence of overweight from 11.8 to 15.5%, but the rate of severe hypoglycemia decreased from 12.1 to 6.9 events/100 patient-years. Associations with other parameters showed a more complex pattern (use of continuous subcutaneous insulin infusion [CSII]) or were not significant.

Area deprivation was associated not only with key outcomes in pediatric type 1 diabetes but also with treatment modalities. Our results show, in particular, that the access to CGMS and CSII could be improved in the most deprived regions in Germany.

To estimate direct medical and indirect costs attributable to diabetes in each U.S. state in total and per person with diabetes.

We used an attributable fraction approach to estimate direct medical costs using data from the 2013 State Health Expenditure Accounts, 2013 Behavioral Risk Factor Surveillance System, and the Centers for Medicare & Medicaid Services’ 2013–2014 Minimum Data Set. We used a human capital approach to estimate indirect costs measured by lost productivity from morbidity (absenteeism, presenteeism, lost household productivity, and inability to work) and premature mortality, using the 2008–2013 National Health Interview Survey, 2013 daily housework value data, 2013 mortality data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research, and mean wages from the 2014 Bureau of Labor Statistics. Costs were adjusted to 2017 U.S. dollars.

The estimated median state economic cost was $5.9 billion, ranging from $694 million to $55.5 billion, in total and $18,248, ranging from $15,418 to $30,915, per person with diabetes. The corresponding estimates for direct medical costs were $2.8 billion (range $0.3–22.9) and $8,544 (range $6,591–12,953) and for indirect costs were $3.0 billion (range $0.4–32.6) and $9,672 (range $7,133–17,962). In general, the estimated state median indirect costs resulting from morbidity were larger than costs from mortality both in total and per person with diabetes.

Economic costs attributable to diabetes were large and varied widely across states. Our comprehensive state-specific estimates provide essential information needed by state policymakers to monitor the economic burden of the disease and to better plan and evaluate interventions for preventing type 2 diabetes and managing diabetes in their states.

Structural brain abnormalities are key risk factors for brain diseases, such as dementia, stroke, and depression, in type 2 diabetes. It is unknown whether structural brain abnormalities already occur in prediabetes. Therefore, we investigated whether both prediabetes and type 2 diabetes are associated with lacunar infarcts (LIs), white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and brain atrophy.

We used data from 2,228 participants (1,373 with normal glucose metabolism [NGM], 347 with prediabetes, and 508 with type 2 diabetes (oversampled); mean age 59.2 ± 8.2 years; 48.3% women) of the Maastricht Study, a population-based cohort study. Diabetes status was determined with an oral glucose tolerance test. Brain imaging was performed with 3 Tesla MRI. Results were analyzed with multivariable logistic and linear regression analyses.

Prediabetes and type 2 diabetes were associated with the presence of LIs (odds ratio 1.61 [95% CI 0.98–2.63] and 1.67 [1.04–2.68], respectively; P_trend = 0.027), larger WMH (β 0.07 log10-transformed mL [log-mL] [95% CI 0.00–0.15] and 0.21 log-mL [0.14–0.28], respectively; P_trend <0.001), and smaller white matter volumes (β –4.0 mL [–7.3 to –0.6] and –7.2 mL [–10.4 to –4.0], respectively; P_trend <0.001) compared with NGM. Prediabetes was not associated with gray matter volumes or the presence of CMBs.

Prediabetes is associated with structural brain abnormalities, with further deterioration in type 2 diabetes. These results indicate that, in middle-aged populations, structural brain abnormalities already occur in prediabetes, which may suggest that the treatment of early dysglycemia may contribute to the prevention of brain diseases.

Type 2 diabetes (T2D) results from progressive loss of β-cell function. The BetaFat study compared gastric banding and metformin for their impact on β-cell function in adults with moderate obesity and impaired glucose tolerance (IGT) or recently diagnosed, mild T2D.

Eighty-eight people aged 21–65 years, BMI 30–40 kg/m², with IGT or diabetes known for <1 year, were randomized to gastric banding or metformin for 2 years. Hyperglycemic clamps (11.1 mmol/L) followed by arginine injection at maximally potentiating glycemia (>25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I).

At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg (P < 0.01). Insulin sensitivity increased 45% in the band group and 25% in the metformin group (P = 0.30 between groups). SSCP adjusted for insulin sensitivity fell slightly but not significantly in each group (P = 0.34 between groups). ACPRmax adjusted for insulin sensitivity fell significantly in the metformin group (P = 0.002) but not in the band group (P = 0.25 between groups). HbA_1c fell at 12 and 24 months in the band group (P < 0.004) but only at 12 months (P < 0.01) in the metformin group (P > 0.14 between groups). Normoglycemia was present in 22% and 15% of band and metformin groups, respectively, at 24 months (P = 0.66 between groups).

Gastric banding and metformin had similar effects to preserve β-cell function and stabilize or improve glycemia over a 2-year period in moderately obese adults with IGT or recently diagnosed, mild T2D.

This study evaluated the long-term safety and efficacy of dapagliflozin as an adjunct to adjustable insulin in patients with type 1 diabetes and inadequate glycemic control.

DEPICT-1 (Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) was a randomized (1:1:1), double-blind, placebo-controlled phase 3 study of dapagliflozin 5 mg and 10 mg in patients with type 1 diabetes (HbA_1c 7.5–10.5% [58–91 mmol/mol]) (NCT02268214). The results of the 52-week study, consisting of the 24-week short-term and 28-week extension period, are reported here.

Of the 833 patients randomized into the study, 708 (85%) completed the 52-week study. Over 52 weeks, dapagliflozin 5 mg and 10 mg led to clinically significant reductions in HbA_1c (difference vs. placebo [95% CI] –0.33% [–0.49, –0.17] [–3.6 mmol/mol (–5.4, –1.9)] and –0.36% [–0.53, –0.20] [–3.9 mmol/mol (–5.8, –2.2)], respectively) and body weight (difference vs. placebo [95% CI] –2.95% [–3.83, –2.06] and –4.54% [–5.40, –3.66], respectively). Serious adverse events were reported in 13.4%, 13.5%, and 11.5% of patients in the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively. Although hypoglycemia events were comparable across treatment groups, more patients in the dapagliflozin groups had events adjudicated as definite diabetic ketoacidosis (DKA; 4.0%, 3.4%, and 1.9% in dapagliflozin 5 mg, 10 mg, and placebo groups, respectively).

Over 52 weeks, dapagliflozin led to improvements in glycemic control and weight loss in patients with type 1 diabetes, while increasing the risk of DKA.

To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D).

The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia.

The observed largest mean placebo-subtracted glycated hemoglobin reductions were –0.28% (95% CI –0.42, –0.15) for 2.5 mg, –0.54% (–0.65, –0.42) for 10 mg, and –0.53% (–0.65, –0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by –1.8/–3.0/–3.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by –6.4/–13.3/–12.7% (all P < 0.0001); and decreased systolic blood pressure by –2.1/–3.9/–3.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo.

Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.

Type 1 diabetes carries a significant risk for cardiovascular mortality, but it is unclear how atherosclerosis associates with microvascular complications. We aimed to determine the relationships between atherosclerotic burden and neuropathy, retinopathy, and diabetic kidney disease (DKD) in adults with a ≥50-year history of type 1 diabetes.

Adults with type 1 diabetes (n = 69) underwent coronary artery calcification (CAC) volume scoring by wide-volume computerized tomography. Microvascular complications were graded as follows: neuropathy by clinical assessment, electrophysiology, vibration and cooling detection thresholds, heart rate variability, and corneal confocal microscopy; retinopathy by ultra–wide-field retinal imaging; and DKD by renal hemodynamic function measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II. The cohort was dichotomized to high (≥300 Agatston units [AU]) or low (<300 AU) CAC and was stratified by diabetes status. A comparator group without diabetes (n = 73) matched for age and sex also underwent all study procedures except for retinal imaging.

CAC scores were higher in participants with type 1 diabetes (median Agatston score 1,000 [interquartile range = 222, 2,373] AU vs. 1 [0.75] AU in comparators, P < 0.001). In participants with type 1 diabetes, high CAC scores associated with markers of neuropathy and retinopathy, but not with DKD, or renal hemodynamic function at baseline or in response to angiotensin II.

The presence of high CAC in adults with longstanding type 1 diabetes was associated with large nerve fiber neuropathy and retinopathy but not with renal hemodynamic function, suggesting that neuropathy, retinopathy, and macrovascular calcification share common risk factors.

To determine whether intraindividual variability in fasting glucose (FG) below the threshold of diabetes is associated with cognitive function in middle adulthood beyond increasing FG.

We studied 3,307 CARDIA (Coronary Artery Risk Development in Young Adults) Study participants (age range 18–30 years and enrolled in 1985–1986) at baseline and calculated two measures of long-term glucose variability: the coefficient of variation about the mean FG (CV-FG) and the absolute difference between successive FG measurements (average real variability [ARV-FG]) before the onset of diabetes over 25 and 30 years of follow-up. Cognitive function was assessed at years 25 (2010–2011) and 30 (2015–2016) with the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment, and category and letter fluency tests. We estimated the association between glucose variability and cognitive function test score with adjustment for clinical and behavioral risk factors, mean FG level, change in FG level, and diabetes development, medication use, and duration.

After multivariable adjustment, 1-SD increment of CV-FG was associated with worse cognitive scores at year 25: DSST, standardized regression coefficient –0.95 (95% CI –1.54, –0.36); RAVLT, –0.14 (95% CI –0.27, –0.02); and Stroop Test, 0.49 (95% CI 0.04, 0.94). Findings were similar between CV-FG with each cognitive test score at year 30 and when we used an alternative measure of variability (ARV-FG) that captures variability in successive FG values.

Higher intraindividual FG variability during young adulthood below the threshold of diabetes was associated with worse processing speed, memory, and language fluency in midlife independent of FG levels.

To examine the course of cardiovascular autonomic neuropathy (CAN) and related cardiometabolic risk factors in patients with type 2 diabetes.

CAN and cardiometabolic risk factors were assessed in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) at 6-year (n = 777) and 13-year (n = 443) follow-up examinations. Cardiovascular autonomic reflex tests (CARTs)—that is, lying to standing, deep breathing, and the Valsalva maneuver—and 2-min resting heart rate variability (HRV) indices were obtained as the main measures of CAN. Risk factors related to CAN status, as determined by CARTs, were studied by using multivariate logistic regressions. The effects of risk factors on continuous CARTs and HRV indices, and their changes over time, were estimated in linear mixed models.

A progressive yet heterogeneous course of CAN occurred between the 6- and 13-year follow-ups. Higher HbA_1c, weight, BMI, and triglycerides were associated with prevalent CAN. No significant effect of risk factors on CARTs was found when they were analyzed as continuous variables. CART indices decreased over time, and a trend of decreasing HRV indices was seen. Higher HbA_1c and BMI were associated with lower HRV index values, but these differences diminished over time.

These data confirm that hyperglycemia, obesity, and hypertriglyceridemia are negatively related to indices of CAN, although these effects diminish over time. The observed heterogeneous course of CAN may challenge the present clinical approach of categorically classifying CARTs to diagnose CAN and the notion of CAN being irreversible.

The prevalence of type 2 diabetes (T2D) is rapidly increasing in sub-Saharan Africa, where sickle cell trait (SCT) is also frequent. Although SCT is generally considered a benign condition, evidence suggests that SCT could exaggerate vascular dysfunction in T2D. However, it remains unclear whether SCT could increase the risk of the development of T2D complications. Therefore, this study was conducted to determine whether T2D complications were more prevalent among Senegalese individuals with SCT and T2D than among those with T2D only.

Rates of hypertension, retinopathy, peripheral neuropathy, peripheral artery disease, and impaired renal function as well as arterial stiffness, blood rheology, and concentrations of plasma advanced glycation end products (AGEs) and cytokines were compared between groups of Senegalese individuals with combined SCT and T2D (T2D-SCT) (n = 60), T2D (n = 52), SCT (n = 53), and neither T2D nor SCT (control) (n = 56). Human aortic endothelial cell (HAEC) expression of inflammatory and adhesion factors was measured after treatment with tumor necrosis factor-α and subjects’ plasma. Effects of AGE inhibition or tiron on HAEC expression of E-selectin were measured.

Retinopathy, hypertension, and reduced renal function were more prevalent, and arterial stiffness, blood viscosity at high shear rates, and thixotropic index were higher, in the SCT group compared with the other groups. Multivariable analysis showed that plasma AGE concentration was significantly associated with arterial stiffness. E-selectin expression was elevated in HAECs treated with T2D-SCT plasma compared with the other groups, but AGE inhibition reversed this.

SCT could potentially augment the risk of the development of T2D-related complications, including retinopathy, nephropathy, and hypertension.

To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein–coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes.

A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina.

The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ≥3–5 x upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ≥3 x ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for ≥10 x ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63).

Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration–mandated CV outcomes trial supported the termination of the fasiglifam clinical program.

Although increasing evidence suggests the association between short-term variability of fasting plasma glucose (FPG) and diabetic complications or mortality, the impact of visit-to-visit variability of FPG on the development of type 2 diabetes (T2D) has not been evaluated.

Our analysis included 131,744 Korean men and women without diabetes using the Korean National Health Insurance System cohort with periodic health examination program. FPG variability was calculated using the coefficient of variation (FPG-CV), SD (FPG-SD), and variability independent of the mean (FPG-VIM).

During the median follow-up time of 8.3 years, Kaplan-Meier curves demonstrated lower disease-free probability in the higher FPG variability group compared with the lower FPG variability group. Multivariable Cox proportional hazards analysis exhibited that the hazard ratio for incident T2D was 1.67 (95% CI 1.58–1.77, P < 0.001) in the highest quartile of FPG-CV compared with the lowest quartile of FPG-CV after adjusting for confounding variables, including mean FPG. The association between FPG variability and the risk of T2D was consistent when modeling using FPG-SD and FPG-VIM in both normal and impaired fasting glucose groups. A 1 SD increase in the FPG-CV was associated with a 24% increased risk of T2D in the fully adjusted model.

Increased variability of FPG is associated with the development of T2D independently of diverse risk factors.

Specific lipid molecular changes leading to type 2 diabetes (T2D) are largely unknown. We assessed lipidome factors associated with future occurrence of T2D in a population at high cardiovascular risk.

We conducted a case-cohort study nested within the PREDIMED trial, with 250 incident T2D cases diagnosed during 3.8 years of median follow-up, and a random sample of 692 participants (639 noncases and 53 overlapping cases) without T2D at baseline. We repeatedly measured 207 plasma known lipid metabolites at baseline and after 1 year of follow-up. We built combined factors of lipid species using principal component analysis and assessed the association between these lipid factors (or their 1-year changes) and T2D incidence.

Baseline lysophosphatidylcholines and lysophosphatidylethanolamines (lysophospholipids [LPs]), phosphatidylcholine-plasmalogens (PC-PLs), sphingomyelins (SMs), and cholesterol esters (CEs) were inversely associated with risk of T2D (multivariable-adjusted P for linear trend ≤0.001 for all). Baseline triacylglycerols (TAGs), diacylglycerols (DAGs), and phosphatidylethanolamines (PEs) were positively associated with T2D risk (multivariable-adjusted P for linear trend <0.001 for all). One-year changes in these lipids showed associations in similar directions but were not significant after adjustment for baseline levels. TAGs with odd-chain fatty acids showed inverse associations with T2D after adjusting for total TAGs.

Two plasma lipid profiles made up of different lipid classes were found to be associated with T2D in participants at high cardiovascular risk. A profile including LPs, PC-PLs, SMs, and CEs was associated with lower T2D risk. Another profile composed of TAGs, DAGs, and PEs was associated with higher T2D risk.

Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes.

Twelve individuals with type 2 diabetes with no history of CV disease and 11 age- and BMI-matched volunteers without diabetes underwent paired hyperinsulinemic-euglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy.

Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased 1.15 ± 0.28 fibers/μm² at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only.

Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short- and medium-term risk of CV mortality.

To pilot test a new closed-loop control technology to validate it for a further large clinical trial.

The t:slim X2 insulin pump with Control-IQ Technology (Tandem Diabetes Care) includes a Dexcom G6 sensor and a closed-loop algorithm implemented in the pump that 1) automates insulin correction boluses, 2) has a dedicated hypoglycemia safety system, and 3) gradually intensifies control overnight, aiming for blood glucose levels of approximately 100–120 mg/dL every morning.

Five patients with type 1 diabetes (mean age 52.8 years, 2/3 male/female, mean A1C 6.5%) used Control-IQ in an outpatient setting (hotel) for approximately 37 h. During the closed loop, mean glucose was 129 mg/dL (135/121 mg/dL during the day/night), time within target range 70–180 mg/dL was 87% (82%/94% during the day/night), and time <60 mg/dL was 1.1% (2.0%/0.0% during the day/night).

Following this pilot trial, Control-IQ was deployed in several studies, including the large-scale National Institutes of Health International Diabetes Closed-Loop (iDCL) Trial.

Autoantibodies directed against tyrosine phosphatase IA-2 antibody (IA-2 Ab) are diagnostic for autoimmune type 1 diabetes. Conventional assays target the intracellular domain of IA-2. Among patients with ketosis-prone diabetes (KPD), characterized by presentation with diabetic ketoacidosis (DKA), >60% of adults lack three classic islet autoantibodies—IA-2, GAD65, and ZnT8 Abs—associated with type 1 diabetes. We aimed to determine whether apparently autoantibody-negative ("A–") KPD patients possess occult IA-2 Ab directed against full-length IA-2 (IA-2FL) or its extracellular domain (IA-2EC).

We developed an assay that targets IA-2FL and IA-2EC and used it to analyze 288 subjects with A– KPD.

Ten A– KPD patients were positive for IA-2EC Ab (3.5%), and three were also positive for IA-2FL Ab (1.0%), similar to frequencies in type 1 and type 2 diabetes.

Measurement of IA-2FL Ab and IA-2EC Ab improves the accuracy of the Aβ classification of KPD patients.

This study aimed to explore the effect of continuous glucose monitors with remote monitoring on psychosocial outcomes in parents of children with type 1 diabetes.

Children with type 1 diabetes, aged 2–12 years, along with their parents, were studied in a randomized crossover study. They participated in two 3-month periods using conventional blood glucose monitoring (control) or the Dexcom G5 Mobile continuous glucose monitoring (CGM) system with remote monitoring (intervention). The primary outcome was parental fear of hypoglycemia score assessed by the Hypoglycemia Fear Survey.

Parental Hypoglycemia Fear Survey scores were lower while the child was using CGM with remote monitoring (P < 0.001). Furthermore, parental health-related quality of life and family functioning, stress, anxiety, and sleep measures also improved significantly after intervention.

CGM with remote monitoring was found to improve multiple measures of quality of life, reduce family stress, and improve parental sleep.

To investigate whether older veterans enrolled in two diabetes prevention programs (DPPs) in the Veterans Health Administration will have similar weight loss as younger veterans.

Post hoc analysis of data from two prospective, pragmatic, nonrandomized studies of behavioral weight management interventions that were delivered in-person (Department of Veterans Affairs [VA]-DPP) or online (Online-DPP), comparing participation and weight loss between participants aged ≥65 years (N = 120) vs. <65 years (N = 258).

Over 70% of participants in both age groups completed eight or more sessions within 6 months; a higher proportion completed eight or more sessions in the Online-DPP intervention than in the VA-DPP intervention (P < 0.05). The overall weight changes at 6 and 12 months were similar across the two age groups: ~5 kg or 5% weight loss compared with baseline (P > 0.05).

DPPs delivered in person or online can be similarly effective in older and younger veterans. Online programs may be an important means to improve the reach of DPPs for older adults.