OBJECTIVE To determine the effect of fitness on the association between BMI and mortality among patients with diabetes. RESEARCH DESIGN AND METHODS We identified 8,528 patients with diabetes (self-report, medication use, or electronic medical record diagnosis) from the Henry Ford ExercIse Testing Project (FIT Project). Patients with a BMI <18.5 kg/m2 or cancer were excluded. Fitness was measured as the METs achieved during a physician-referred treadmill stress test and categorized as low (<6), moderate (6–9.9), and high (≥10). Adjusted hazard ratios for mortality were calculated using standard BMI (kilograms per meter squared) cutoffs of normal (18.5–24.9), overweight (25–29.9), and obese (≥30). Adjusted splines centered at 22.5 kg/m2 were used to examine BMI as a continuous variable. RESULTS Patients had a mean age of 58 ± 11 years (49% women) with 1,319 deaths over a mean follow-up of 10.0 ± 4.1 years. Overall, obese patients had a 30% lower mortality hazard ( P < 0.001) compared with normal-weight patients. In adjusted spline modeling, higher BMI as a continuous variable was predominantly associated with a lower mortality risk in the lowest fitness group and among patients with moderate fitness and BMI ≥30 kg/m2. Compared with the lowest fitness group, patients with higher fitness had an ∼50% (6–9.9 METs) and 70% (≥10 METs) lower mortality hazard regardless of BMI ( P < 0.001). CONCLUSIONS Among patients with diabetes, the obesity paradox was less pronounced for patients with the highest fitness level, and these patients also had the lowest risk of mortality.

OBJECTIVE Dual incretin receptor agonists in clinical development have shown reductions in body weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the impact of glucose-dependent insulinotropic polypeptide (GIP) receptor activation remains unclear. Here, we evaluated the effects of high-dose exogenous GIP on energy intake, energy expenditure, plasma glucose, and glucose-regulating hormones in patients with type 2 diabetes treated with a long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist. RESEARCH DESIGN AND METHODS In a randomized, double-blind design, men with type 2 diabetes ( n = 22, mean ± SEM HbA1c 6.8 ± 0.1% [51 ± 1.5 mmol/mol]) treated with metformin and long-acting GLP-1R agonists were subjected to two 5-h continuous infusions (separated by a washout period of ≥3 days): one with GIP (6 pmol/kg/min) and another with saline (placebo). After 60 min of infusion, a liquid mixed-meal test was performed and after 270 min of infusion, an ad libitum meal was served for evaluation of energy intake (primary end point). RESULTS Energy intake was similar during GIP and placebo infusion (648 ± 74 kcal vs. 594 ± 55 kcal, respectively; P = 0.480), as were appetite measures and energy expenditure. Plasma glucagon and glucose were higher during GIP infusion compared with placebo infusion ( P = 0.026 and P = 0.017) as assessed by area under the curve. CONCLUSIONS In patients with type 2 diabetes, GIP infusion on top of treatment with metformin and a long-acting GLP-1R agonist did not affect energy intake, appetite, or energy expenditure but increased plasma glucose compared with placebo. These results indicate no acute beneficial effects of combining GIP and GLP-1.

This Consensus Report is intended to provide clinical professionals with evidence-based guidance about individualizing nutrition therapy for adults with diabetes or prediabetes. Strong evidence supports the efficacy and cost-effectiveness of nutrition therapy as a component of quality diabetes care, including its integration into the medical management of diabetes; therefore, it is important that all members of the health care team know and champion the benefits of nutrition therapy and key nutrition messages. Nutrition counseling that works toward improving or maintaining glycemic targets, achieving weight management goals, and improving cardiovascular risk factors (e.g., blood pressure, lipids, etc.) within individualized treatment goals is recommended for all adults with diabetes and prediabetes. Though it might simplify messaging, a “one-size-fits-all” eating plan is not evident for the prevention or management of diabetes, and it is an unrealistic expectation given the broad spectrum of people affected by diabetes and prediabetes, their cultural backgrounds, personal preferences, co-occurring conditions (often referred to as comorbidities), and socioeconomic settings in which they live. Research provides clarity on many food choices and eating patterns that can help people achieve health goals and quality of life. The American Diabetes Association (ADA) emphasizes that medical nutrition therapy (MNT) is fundamental in the overall diabetes management plan, and the need for MNT should be reassessed frequently by health care providers in collaboration with people with diabetes across the life span, with special attention during times of changing health status and life stages (1–3). This Consensus Report now includes information on prediabetes, and previous ADA nutrition position statements, the last of which was published in 2014 (4), did not. Unless otherwise noted, the research reviewed was limited to those studies conducted in adults diagnosed with prediabetes, type 1 diabetes, and/or type 2 diabetes. Nutrition therapy for children with diabetes or women …

OBJECTIVE The American Diabetes Association recommends individuals with type 1 diabetes (T1D) adjust insulin for dietary fat; however, optimal adjustments are not known. This study aimed to determine 1 ) the relationship between the amount and type of dietary fat and glycemia and 2 ) the optimal insulin adjustments for dietary fat. RESEARCH DESIGN AND METHODS Adults with T1D using insulin pump therapy attended the research clinic on 9–12 occasions. On the first six visits, participants consumed meals containing 45 g carbohydrate with 0 g, 20 g, 40 g, or 60 g fat and either saturated, monounsaturated, or polyunsaturated fat. Insulin was dosed using individual insulin/carbohydrate ratio as a dual-wave 50/50% over 2 h. On subsequent visits, participants repeated the 20–60-g fat meals with the insulin dose estimated using a model predictive bolus, up to twice per meal, until glycemic control was achieved. RESULTS With the same insulin dose, increasing the amount of fat resulted in a significant dose-dependent reduction in incremental area under the curve for glucose (iAUCglucose) in the early postprandial period (0–2 h; P = 0.008) and increase in iAUCglucose in the late postprandial period (2–5 h; P = 0.004). The type of fat made no significant difference to the 5-h iAUCglucose. To achieve glycemic control, on average participants required dual-wave insulin bolus: for 20 g fat, +6% insulin, 74/26% over 73 min; 40 g fat, +6% insulin, 63/37% over 75 min; and 60 g fat, +21% insulin, 49/51% over 105 min. CONCLUSIONS This study provides clinical guidance for mealtime insulin dosing recommendations for dietary fat in T1D.

OBJECTIVE To determine the correlation between urinary and serum placental growth factor (PlGF) and investigate the predictive value as pregnancy progresses of urinary PlGF compared with serum PlGF, soluble fms-like tyrosine kinase 1 (sFLT-1), and the sFLT-1–to–PlGF ratio for the outcome of preeclampsia in women with preexisting diabetes. RESEARCH DESIGN AND METHODS A multicenter prospective cohort study was conducted of 158 women with preexisting insulin-requiring diabetes (41 with type 1 and 117 with type 2). Urinary PlGF and serum PlGF, sFLT-1, and the sFLT-1–to–PlGF ratio were assessed four times (14, 24, 30, and 36 weeks’ gestation), and the association with the outcome of preeclampsia was investigated. RESULTS A correlation between urinary and serum PlGF was demonstrated from 24 weeks’ gestation onward ( P < 0.001). At all time points, those who developed preeclampsia had lower serum PlGF levels ( P < 0.05), and receiver operating characteristic curves demonstrated that serum PlGF in this cohort performed better than the serum sFLT-1–to–PlGF ratio as a predictive test for preeclampsia. Preconception HbA1c ≥6.5% (48 mmol/mol) was an important discriminative predictor for preeclampsia ( P = 0.01). CONCLUSIONS This study prospectively describes the longitudinal changes in urinary PlGF alongside serum angiogenic markers throughout pregnancy in women with preexisting diabetes. We demonstrate correlation between urinary and serum PlGF and that in women with preexisting diabetes in pregnancy, serum PlGF is a better predictor of preeclampsia than the sFLT-1–to–PlGF ratio.

OBJECTIVE Conventional gestational diabetes mellitus (GDM) management focuses on managing blood glucose in order to prevent adverse outcomes. We hypothesized that excessive weight gain at first presentation with GDM (excessive gestational weight gain [EGWG]) and continued EGWG (cEGWG) after commencing GDM management would increase the risk of adverse outcomes, despite treatment to optimize glycemia. RESEARCH DESIGN AND METHODS Data collected prospectively from pregnant women with GDM at a single institution were analyzed. GDM was diagnosed on the basis of Australasian Diabetes in Pregnancy Society 1998 guidelines (1992–2015). EGWG means having exceeded the upper limit of the Institute of Medicine–recommended target ranges for the entire pregnancy, by GDM presentation. The relationship between EGWG and antenatal 75-g oral glucose tolerance test (oGTT) values and adverse outcomes was evaluated. Relationships were examined between cEGWG, insulin requirements, and large-for-gestational-age (LGA) infants. RESULTS Of 3,281 pregnant women, 776 (23.6%) had EGWG. Women with EGWG had higher mean fasting plasma glucose (FPG) on oGTT (5.2 mmol/L [95% CI 5.1–5.3] vs. 5.0 mmol/L [95% CI 4.9–5.0]; P < 0.01), after adjusting for confounders, and more often received insulin therapy (47.0% vs. 33.6%; P < 0.0001), with an adjusted odds ratio (aOR) of 1.4 (95% CI 1.1–1.7; P < 0.01). aORs for each 2-kg increment of cEGWG were a 1.3-fold higher use of insulin therapy (95% CI 1.1–1.5; P < 0.001), an 8-unit increase in final daily insulin dose (95% CI 5.4–11.0; P < 0.0001), and a 1.4-fold increase in the rate of delivery of LGA infants (95% CI 1.2–1.7; P < 0.0001). CONCLUSIONS The absence of EGWG and restricting cEGWG in GDM have a mitigating effect on oGTT-based FPG, the risk of having an LGA infant, and insulin requirements.

OBJECTIVE Identifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population. RESEARCH DESIGN AND METHODS Swedish patients ( n = 3,933) aged 1–18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK , HNF1A , and HNF4A , through either routine clinical or research testing. RESULTS The minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 × 10−44), HbA1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 × 10−20), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 × 10−19), parental diabetes (63% vs. 12%; P = 1 × 10−15), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment. CONCLUSIONS At diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four islet autoantibodies is an effective strategy for not missing MODY but will result in a lower detection rate. Identifying MODY results in excellent long-term glycemic control without insulin.

OBJECTIVE Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. RESEARCH DESIGN AND METHODS We studied 706 single autoantibody–positive pediatric TrialNet participants (ages 1.6–18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. RESULTS At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was −9.2 to 15.6 kg/m2 (median −1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA ( P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. CONCLUSIONS These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity.

OBJECTIVE Assess the efficacy of inControl AP: a mobile closed-loop control (CLC) system. RESEARCH DESIGN AND METHODS This protocol, [NCT02985866][1], is a 3-month parallel group, multicenter, randomized unblinded trial designed to compare mobile CLC with sensor augmented pump (SAP) therapy. Eligibility criteria were type 1 diabetes for at least 1 year, use of insulin pumps for at least 6 months, age ≥14 years, and baseline HbA1c <10.5% (91 mmol/mol). The study was designed to assess two coprimary outcomes: superiority of CLC over SAP in continuous glucose monitor (CGM)–measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L. RESULTS Between November 2017 and May 2018, 127 participants were randomly assigned 1:1 to CLC ( n = 65) versus SAP ( n = 62); 125 participants completed the study. CGM time below 3.9 mmol/L was 5.0% at baseline and 2.4% during follow-up in the CLC group vs. 4.7% and 4.0%, respectively, in the SAP group (mean difference −1.7% [95% CI −2.4, −1.0%]; P < 0.0001 for superiority). CGM time above 10 mmol/L was 40% at baseline and 34% during follow-up in the CLC group vs. 43% and 39%, respectively, in the SAP group (mean difference −3.0% [95% CI −6.1, +0.1%]; P < 0.0001 for noninferiority). One severe hypoglycemic event occurred in the CLC group, which was unrelated to the study device. CONCLUSIONS In meeting its coprimary end points, superiority of CLC over SAP in CGM-measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L, the study has demonstrated that mobile CLC is feasible and could offer certain usability advantages over embedded systems, provided the connectivity between system components is stable. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02985866&atom=%2Fdiacare%2Fearly%2F2020%2F01%2F13%2Fdc19-1310.atom

OBJECTIVE To determine the prevalence of cognitive deficits and traditional diabetic complications and the association between metabolic factors and these outcomes. RESEARCH DESIGN AND METHODS We performed a cross-sectional study in severely obese individuals before bariatric surgery. Lean control subjects were recruited from a research website. Cognitive deficits were defined by the National Institutes of Health (NIH) Toolbox (less than the fifth percentile for lean control subjects). Cardiovascular autonomic neuropathy (CAN) was defined by an expiration-to-inspiration (E-to-I) ratio of less than the fifth percentile for lean control subjects. Retinopathy was based on retinal photographs and nephropathy on the estimated glomerular filtration rate (<60 mg/dL) and/or the albumin-to-creatinine ratio (ACR) (≥30 mg/g). NIH Toolbox, E-to-I ratio, mean deviation on frequency doubling technology testing, and ACR were used as sensitive measures of these outcomes. We used multivariable linear regression to explore associations between metabolic factors and these outcomes. RESULTS We recruited 138 severely obese individuals and 46 lean control subjects. The prevalence of cognitive deficits, CAN, retinopathy, and nephropathy were 6.5%, 4.4%, 0%, and 6.5% in lean control subjects, 22.2%, 18.2%, 0%, and 6.1% in obese participants with normoglycemia, 17.7%, 21.4%, 1.9%, and 17.9% in obese participants with prediabetes, and 25.6%, 31.9%, 6.1%, and 16.3% in obese participants with diabetes. Waist circumference was significantly associated with cognitive function (−1.48, 95% CI −2.38, −0.57) and E-to-I ratio (−0.007, 95% CI −0.012, −0.002). Prediabetes was significantly associated with retinal function (−1.78, 95% CI −3.56, −0.002). CONCLUSIONS Obesity alone is likely sufficient to cause cognitive deficits but not retinopathy or nephropathy. Central obesity is the key metabolic risk factor.

OBJECTIVE Neonatal diabetes has been shown to be associated with high neuropsychiatric morbidity in a genotype-phenotype–dependent manner. However, the specific impact of different mutations on intellectual functioning is still insufficiently characterized. Specifically, only a small number of subjects with developmental delay have been comprehensively assessed, creating a knowledge gap for patients carrying the heaviest burden. RESEARCH DESIGN AND METHOD We here assessed the intellectual functioning and mental health of the complete Norwegian population of KATP channel neonatal diabetes. Eight sulfonylurea-treated children (five with the p.V59M genotype [ KCNJ11 ]) were assessed using age-matched control subjects with type 1 diabetes. The investigations included a physical and motor developmental examination, cerebral MRI, psychometrical examination, and questionnaires assessing intellectual capabilities and psychiatric morbidity. RESULTS A strong genotype-phenotype correlation was found, revealing the p.V59M genotype as highly associated with substantial intellectual disability, with no significant correlation with the time of sulfonylurea initiation. Consistent with previous studies, other genotypes were associated with minor cognitive impairment. Cerebral MRI verified normal brain anatomy in all but one. CONCLUSIONS We here presented a comprehensive assessment of intellectual functioning in the largest cohort of p.V59M subjects to date. The level of intellectual disability revealed not only changes the interpretation of other psychological measures but downplays a strong protective effect of sulfonylurea. Within the scope of this study, we could not find evidence supporting an early treatment start to be beneficial, although a weaker effect cannot be ruled out.

OBJECTIVE Previous studies suggested that childhood prediabetes might develop prior to obesity and be associated with relative insulin deficiency. We proposed that the insulin-deficient phenotype is genetically determined and tested this hypothesis by longitudinal modeling of insulin and glucose traits with diabetes risk genotypes in the EarlyBird cohort. RESEARCH DESIGN AND METHODS EarlyBird is a nonintervention prospective cohort study that recruited 307 healthy U.K. children at 5 years of age and followed them throughout childhood. We genotyped 121 single nucleotide polymorphisms (SNPs) previously associated with diabetes risk, identified in the adult population. Association of SNPs with fasting insulin and glucose and HOMA indices of insulin resistance and β-cell function, available from 5 to 16 years of age, were tested. Association analysis with hormones was performed on selected SNPs. RESULTS Several candidate loci influenced the course of glycemic and insulin traits, including rs780094 (GCKR), rs4457053 (ZBED3), rs11257655 (CDC123), rs12779790 (CDC123 and CAMK1D), rs1111875 (HHEX), rs7178572 (HMG20A), rs9787485 (NRG3), and rs1535500 (KCNK16). Some of these SNPs interacted with age, the growth hormone–IGF-1 axis, and adrenal and sex steroid activity. CONCLUSIONS The findings that genetic markers influence both elevated and average courses of glycemic traits and β-cell function in children during puberty independently of BMI are a significant step toward early identification of children at risk for diabetes. These findings build on our previous observations that pancreatic β-cell defects predate insulin resistance in the onset of prediabetes. Understanding the mechanisms of interactions among genetic factors, puberty, and weight gain would allow the development of new and earlier disease-management strategies in children.

OBJECTIVE Plasma protein N -glycan profiling integrates information on enzymatic protein glycosylation, which is a highly controlled ubiquitous posttranslational modification. Here we investigate the ability of the plasma N -glycome to predict incidence of type 2 diabetes and cardiovascular diseases (CVDs; i.e., myocardial infarction and stroke). RESEARCH DESIGN AND METHODS Based on the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort ( n = 27,548), we constructed case-cohorts including a random subsample of 2,500 participants and all physician-verified incident cases of type 2 diabetes ( n = 820; median follow-up time 6.5 years) and CVD ( n = 508; median follow-up time 8.2 years). Information on the relative abundance of 39 N -glycan groups in baseline plasma samples was generated by chromatographic profiling. We selected predictive N -glycans for type 2 diabetes and CVD separately, based on cross-validated machine learning, nonlinear model building, and construction of weighted prediction scores. This workflow for CVD was applied separately in men and women. RESULTS The N -glycan–based type 2 diabetes score was strongly predictive for diabetes risk in an internal validation cohort (weighted C index 0.83, 95% CI 0.78–0.88), and this finding was externally validated in the Finland Cardiovascular Risk Study (FINRISK) cohort. N -glycans were moderately predictive for CVD incidence (weighted C indices men: 0.66, 95% CI 0.60–0.72; women: 0.64, 95% CI 0.55–0.73). Information on the selected N -glycans improved the accuracy of established and clinically applied risk prediction scores for type 2 diabetes and CVD. CONCLUSIONS Selected N -glycans improve type 2 diabetes and CVD prediction beyond established risk markers. Plasma protein N -glycan profiling may thus be useful for risk stratification in the context of precisely targeted primary prevention of cardiometabolic diseases.

OBJECTIVE To assess the impact of a telemedicine visit using the platform Diabetic compared with a face-to-face visit on clinical outcomes, patients’ health-related quality of life (HRQoL), and physicians’ satisfaction in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS PLATEDIAN (Telemedicine on Metabolic Control in Type 1 Diabetes Mellitus Andalusian Patients) ([NCT03332472][1]) was a multicenter, randomized, 6-month follow-up, open-label, parallel-group controlled study performed in patients with type 1 diabetes with suboptimal metabolic control (HbA1c <8% [<64 mmol/mol]), treated with multiple daily injections. A total of 388 patients were assessed for eligibility; 379 of them were randomized 1:1 to three face-to-face visits (control cohort [CC]) ( n = 167) or the replacement of an intermediate face-to-face visit by a telemedicine visit using Diabetic (intervention cohort [IC]) ( n = 163). The primary efficacy end point was the mean change of HbA1c levels from baseline to month 6. Other efficacy and safety end points were mean blood glucose, glucose variability, episodes of hypoglycemia and hyperglycemia, patient-reported outcomes, and physicians’ satisfaction. RESULTS At month 6, the mean change in HbA1c levels was −0.04 ± 0.5% (−0.5 ± 5.8 mmol/mol) in the CC and 0.01 ± 0.6% (0.1 ± 6.0 mmol/mol) in the IC ( P = 0.4941). The number of patients who achieved HbA1c <7% (<53 mmol/mol) was 73 and 78 in the CC and IC, respectively. Significant differences were not found regarding safety end points at 6 months. Changes in HRQoL between the first visit and final visit did not differ between cohorts, and, regarding fear of hypoglycemia (FH-15 score ≥28), statistically significant differences observed at baseline remained unchanged at 6 months ( P < 0.05). CONCLUSIONS The use of telemedicine in patients with type 1 diabetes with HbA1c <8% (<64 mmol/mol) provides similar efficacy and safety outcomes as face-to-face visits. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03332472&atom=%2Fdiacare%2Fearly%2F2020%2F01%2F02%2Fdc19-0739.atom

OBJECTIVE Diabetes is a major risk factor for renal function decline and failure. The availability of multiplex panels of biochemical markers provides the opportunity to identify novel biomarkers that can better predict changes in renal function than routinely available clinical markers. RESEARCH DESIGN AND METHODS The concentration of 239 biochemical markers was measured in stored serum from participants in the biomarker substudy of Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial. Repeated-measures mixed-effects models were used to compute the annual change in eGFR (measured as mL/min/1.73 m2/year) for the 7,482 participants with a recorded baseline and follow-up eGFR. Linear regression models using forward selection were used to identify the independent biomarker determinants of the annual change in eGFR after accounting for baseline HbA1c, baseline eGFR, and routinely measured clinical risk factors. The incidence of the composite renal outcome (i.e., renal replacement therapy, renal death, renal failure, albuminuria progression, doubling of serum creatinine) and death within each fourth of change in eGFR predicted from these models was also estimated. RESULTS During 6.2 years of median follow-up, the median annual change in eGFR was −0.18 mL/min/1.73 m2/year. Fifteen biomarkers independently predicted eGFR decline after accounting for cardiovascular risk factors as did 12 of these plus 1 additional biomarker after accounting for renal risk factors. Every 0.1 mL/min/1.73 m2 predicted annual fall in eGFR predicted a 13% (95% CI 12, 14%) higher mortality. CONCLUSIONS Adding up to 16 biomarkers to routinely measured clinical risk factors improves the prediction of annual change in eGFR in people with dysglycemia.

OBJECTIVE Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NASH have increased risk for adverse clinical outcomes, leading to higher risk for mortality and morbidity. We built a Markov model with 1-year cycles and 20-year horizon to estimate the economic burden of NASH with T2DM in the U.S. RESEARCH DESIGN AND METHODS Cohort size was determined by population size, prevalence of T2DM, and prevalence and incidence of NASH in 2017. The model includes 10 health states—NAFL, NASH fibrosis stages F0 through F3, compensated and decompensated cirrhosis, hepatocellular carcinoma, 1 year post–liver transplant, and post–liver transplant—as well as liver-related, cardiovascular, and background mortality. Transition probabilities were calculated from meta-analyses and literature. Annual costs for NASH and T2DM were taken from literature and billing codes. RESULTS We estimated that there were 18.2 million people in the U.S. living with T2DM and NAFLD, of which 6.4 million had NASH. Twenty-year costs for NAFLD in these patients were $55.8 billion. Over the next 20 years, NASH with T2DM will account for 65,000 transplants, 1.37 million cardiovascular-related deaths, and 812,000 liver-related deaths. CONCLUSIONS This model predicts significant clinical and economic burden due to NASH with T2DM over the next 20 years. In fact, this burden may be greater since we assumed conservative inputs for our model and did not increase costs or the incidence of T2DM over time. It is highly likely that interventions reducing morbidity and mortality in NASH patients with T2DM could potentially reduce this projected clinical and economic burden.

OBJECTIVE To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Medical resource use data and responses to the EuroQol 5-Dimension (EQ-5D) instrument were collected at baseline and throughout the trial. Medical resources and medications were assigned values by using U.S. Medicare payments and wholesale acquisition costs, respectively. Secondary analyses used English costs. RESULTS Patients were followed for an average of 3.3 years, during which time those randomized to EQW experienced 0.41 fewer inpatient days (7.05 vs. 7.46 days; relative rate ratio 0.91; P = 0.05). Rates of outpatient medical visits were similar, as were total inpatient and outpatient costs. Mean costs for nonstudy diabetes medications over the study period were ∼$1,600 lower with EQW than with placebo ( P = 0.01). Total within-study costs, excluding study medication, were lower in the EQW arm than in the placebo arm ($28,907 vs. $30,914; P ≤ 0.01). When including the estimated cost of EQW, total mean costs were significantly higher in the EQW group than in the placebo group ($42,697 vs. $30,914; P < 0.01). With English costs applied, mean total costs, including exenatide costs, were £1,670 higher in the EQW group than the placebo group (£10,874 vs. £9,204; P < 0.01). There were no significant differences in EQ-5D health utilities between arms over time. CONCLUSIONS Medical costs were lower in the EQW arm than the placebo arm, but total costs were significantly higher once the cost of branded exenatide was incorporated.

The Professional Practice Committee (PPC) of the American Diabetes Association (ADA) is responsible for the “Standards of Medical Care in Diabetes,” referred to as the Standards of Care. The PPC is a multidisciplinary expert committee comprised of physicians, diabetes educators, and others who have expertise in a range of areas, including, but not limited to, adult and pediatric endocrinology, epidemiology, public health, cardiovascular risk management, microvascular complications, preconception and pregnancy care, weight management and diabetes prevention, and use of technology in diabetes management. Appointment to the PPC is based on excellence in clinical practice and research. Although the primary role of the PPC members is to review and update the Standards of Care, they may also be involved in ADA statements, reports, and reviews.

OBJECTIVE This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 (interquartile range 5.7–10.6) years with available growth data. Of these, 761 (10.1%) children developed IA, and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children’s individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D. RESULTS A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only. CONCLUSIONS Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.

OBJECTIVE Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans. RESEARCH DESIGN AND METHODS Fifteen obese adults received intravenous infusion of either saline or GLP-1 (1.2 pmol/kg/min) for 150 min with or without a euglycemic insulin clamp (1 mU/kg/min) superimposed over the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity and blood flow, brachial artery diameter and blood flow, and pulse wave velocity (PWV) were determined. RESULTS Insulin failed to change MBV or flow in either skeletal or cardiac muscle, confirming the presence of microvascular insulin resistance. GLP-1 infusion alone increased MBV by ∼30% and ∼40% in skeletal and cardiac muscle, respectively, with no change in flow velocity, leading to a significant increase in microvascular blood flow in both skeletal and cardiac muscle. Superimposition of insulin to GLP-1 infusion did not further increase MBV or flow in either skeletal or cardiac muscle but raised the steady-state glucose infusion rate by ∼20%. Insulin, GLP-1, and GLP-1 + insulin infusion did not alter brachial artery diameter and blood flow or PWV. The vasodilatory actions of GLP-1 are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.

OBJECTIVE In children with type 1 diabetes (T1D), severe hypoglycemia (SH) is associated with poorer cognition, but the association of SH with cognitive function in late life is unknown. Given the increasing life expectancy in T1D, understanding the role of SH in brain health is crucial. RESEARCH DESIGN AND METHODS We examined the association between SH and cognitive function in 718 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Subjects self-reported recent SH (previous 12 months) and lifetime history of SH resulting in inpatient/emergency department utilization. Global and domain-specific cognition (language, executive function, episodic memory, and simple attention) were assessed. The associations of SH with cognitive function and impaired cognition were evaluated via linear and logistic regression models, respectively. RESULTS Thirty-two percent of participants (mean age 67.2 years) reported recent SH and 50% reported lifetime SH. Compared with those with no SH, subjects with a recent SH history had significantly lower global cognition scores. Domain-specific analyses revealed significantly lower scores on language, executive function, and episodic memory with recent SH exposure and significantly lower executive function with lifetime SH exposure. Recent SH was associated with impaired global cognition (odds ratio [OR] 3.22, 95% CI 1.30, 7.94) and cognitive impairment on the language domain (OR 3.15, 95% CI 1.19, 8.29). CONCLUSIONS Among older adults with T1D, recent SH and lifetime SH were associated with worse cognition. Recent SH was associated with impaired global cognition. These findings suggest a deleterious role of SH on the brain health of older patients with T1D and highlight the importance of SH prevention.

OBJECTIVE Previous randomized trials found that treating periodontitis improved glycemic control in patients with type 2 diabetes (T2D), thus lowering the risks of developing T2D-related microvascular diseases and cardiovascular disease (CVD). Some payers in the U.S. have started covering nonsurgical periodontal treatment for those with chronic conditions, such as diabetes. We sought to identify the cost-effectiveness of expanding periodontal treatment coverage among patients with T2D. RESEARCH DESIGN AND METHODS A cost-effectiveness analysis was conducted to estimate lifetime costs and health gains using a stochastic microsimulation model of oral health conditions, T2D, T2D-related microvascular diseases, and CVD of the U.S. population. Model parameters were obtained from the nationally representative National Health and Nutrition Examination Survey (NHANES) (2009–2014) and randomized trials of periodontal treatment among patients with T2D. RESULTS Expanding periodontal treatment coverage among patients with T2D and periodontitis would be expected to avert tooth loss by 34.1% (95% CI −39.9, −26.5), and microvascular diseases by 20.5% (95% CI −31.2, −9.1), 17.7% (95% CI −32.7, −4.7), and 19.2% (95% CI −18.4, −3.5) for nephropathy, neuropathy, and retinopathy, respectively. Providing periodontal treatment to the target population would be cost saving from a health care perspective at a total net savings of 5,904 USD (95% CI −6,039, −5,769) with an estimated gain of 0.6 QALYs per capita (95% CI 0.5, 0.6). CONCLUSIONS Providing nonsurgical periodontal treatment to patients with T2D and periodontitis would be expected to significantly reduce tooth loss and T2D-related microvascular diseases via improved glycemic control. Encouraging patients with T2D and poor oral health conditions to receive periodontal treatment would improve health outcomes and still be cost saving or cost-effective.

OBJECTIVE The effective redesign of primary care delivery systems to improve diabetes care requires an understanding of which particular components of delivery consistently lead to better clinical outcomes. We identified associations between common systems of care management (SysCMs) and the frequency of meeting standardized performance targets for Optimal Diabetes Care (NQF#0729) in primary care practices. RESEARCH DESIGN AND METHODS A validated survey of 585 eligible family or general internal medicine practices seeing ≥30 adult patients with diabetes in or near Minnesota during 2017 evaluated the presence of 62 SysCMs. From 419 (72%) practices completing the survey, NQF#0729 was determined in 396 (95%) from electronic health records, including 215,842 patients with type 1 or type 2 diabetes. RESULTS Three SysCMs were associated with higher rates of meeting performance targets across all practices: 1 ) a systematic process for shared decision making with patients ( P = 0.001), 2 ) checklists of tests or interventions needed for prevention or monitoring of diabetes ( P = 0.002), and 3 ) physician reminders of guideline-based age-appropriate risk assessments due at the patient visit ( P = 0.002). When all three were in place, an additional 10.8% of the population achieved recommended performance measures. In subgroup analysis, 15 additional SysCMs were associated with better care in particular types of practices. CONCLUSIONS Diabetes care outcomes are better in primary care settings that use a patient-centered approach to systematically engage patients in decision making, remind physicians of age-appropriate risk assessments, and provide checklists for recommended diabetes interventions. Practice size and location are important considerations when redesigning delivery systems to improve performance.

OBJECTIVE We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk. RESEARCH DESIGN AND METHODS In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs. RESULTS SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94–1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38–2.42], P < 0.001), CV death (1.60 [1.11–2.30], P = 0.012), and hHF (2.09 [1.37–3.17], P = 0.001), while nonfatal MI (2.02 [1.35–3.01], P = 0.001), nonfatal stroke (2.30 [1.25–4.23], P = 0.007), hACS (2.00 [1.39–2.90], P < 0.001), and hHF (3.24 [1.98–5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without. CONCLUSIONS These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores.

OBJECTIVE In 2016, nationwide reimbursement of intermittently scanned continuous glucose monitoring (isCGM) for people living with type 1 diabetes treated in specialist diabetes centers was introduced in Belgium. We undertook a 12-month prospective observational multicenter real-world study to investigate impact of isCGM on quality of life and glycemic control. RESEARCH DESIGN AND METHODS Between July 2016 and July 2018, 1,913 adults with type 1 diabetes were consecutively recruited in three specialist diabetes centers. Demographic, metabolic, and quality of life data were collected at baseline, 6 months, and 12 months of standardized clinical follow-up. The primary end point was evolution of quality of life from baseline to 12 months. Secondary outcome measures were, among others, change in HbA1c, time spent in different glycemic ranges, occurrence of acute diabetes complications, and work absenteeism. RESULTS General and diabetes-specific quality of life was high at baseline and remained stable, whereas treatment satisfaction improved ( P < 0.0001). Admissions for severe hypoglycemia and/or ketoacidosis were rare in the year before study ( n = 63 out of 1,913; 3.3%), but decreased further to 2.2% ( n = 37 out of 1,711; P = 0.031). During the study, fewer people reported severe hypoglycemic events ( n = 280 out of 1,913 [14.6%] vs. n = 134 out of 1,711 [7.8%]; P < 0.0001) or hypoglycemic comas ( n = 52 out of 1,913 [2.7%] vs. n = 18 out of 1,711 [1.1%]; P = 0.001) while maintaining HbA1c levels. Fewer people were absent from work ( n = 111 out of 1,913 [5.8%] vs. n = 49 out of 1,711 [2.9%]; P < 0.0001). Time spent in hypoglycemia significantly decreased in parallel with less time in range and more time in hyperglycemia. Eleven percent ( n = 210) of participants experienced skin reactions, leading to stopping of isCGM in 22 participants (1%). CONCLUSIONS Nationwide unrestricted reimbursement of isCGM in people with type 1 diabetes treated in specialist diabetes centers results in higher treatment satisfaction, less severe hypoglycemia, and less work absenteeism, while maintaining quality of life and HbA1c.

OBJECTIVE Haptoglobin is an acute-phase reactant with pleiotropic functions. We aim to study whether urine haptoglobin may predict risk of mortality in people with type 2 diabetes. RESEARCH DESIGN AND METHODS We employed a transethnic approach with a cohort of Asian origin (Singapore) ( N = 2,061) and a cohort of European origin (France) ( N = 1,438) included in the study. We used survival analyses to study the association of urine haptoglobin with risk of all-cause and cause-specific mortality. RESULTS A total of 365 and 525 deaths were registered in the Singapore cohort (median follow-up 7.5 years [interquartile range 3.5–12.8]) and French SURDIAGENE cohort (median follow-up 6.8 years [interquartile range 4.3–10.5], respectively. Singapore participants with urine haptoglobin in quartiles 2 to 4 had higher risk for all-cause mortality compared with quartile 1 (unadjusted hazard ratio [HR] 1.47 [95% CI 1.02–2.11], 2.28 [1.62–3.21], and 4.64 [3.39–6.35], respectively). The association remained significant in quartile 4 after multiple adjustments (1.68 [1.15–2.45]). Similarly, participants in the French cohort with haptoglobin in quartile 4 had significantly higher hazards for all-cause mortality compared with quartile 1 (unadjusted HR 2.67 [2.09–3.42] and adjusted HR 1.49 [1.14–1.96]). In both cohorts, participants in quartile 4 had a higher risk of mortality attributable to cardiovascular disease and infection but not malignant tumor. CONCLUSIONS Urine haptoglobin predicts risk of mortality independent of traditional risk factors, suggesting that it may potentially be a novel biomarker for risk of mortality in patients with type 2 diabetes.

OBJECTIVE To investigate the association of the cardiovascular risk factor Lipoprotein(a) [Lp (a)] and vascular complications in patients with type 1 diabetes mellitus. RESEARCH DESIGN AND METHODS Patients with type 1 diabetes mellitus receiving regular care were recruited in this observational cross-sectional study and divided into four groups according to their Lp(a) levels in nmol/L (Very Low <10; Low 10-30; Intermediate 30-120; High>120). Prevalence of vascular complications was compared between the groups. In addition, the association between metabolic control, measured as HbA1c, and Lp(a) was studied. RESULTS The patients (n=1860) had a median age 48 years, diabetes duration 25 years, and HbA1c 7.8% (61 mmol/mol). The median Lp(a) (interquartile range) was 19 (10-71) nmol/L. No significant differences between males and females were observed, but Lp(a) levels increased with increasing age. Patients in the high Lp(a) group had higher prevalence of complications than patients in the very low Lp(a) group. The age- and smoking-status-adjusted relative risk ratio of having any macrovascular disease was 1.51 (confidence interval, CI 1.01-2.28, p=0.048), coronary heart disease 1.70 (CI 0.97-3.00, p=0.063), albuminuria 1.68 (CI 1.12-2.50, p=0.01) and calcified aortic valve disease 2.03 (CI 1.03-4.03; p=0.042). Patients with good metabolic control, HbA1c <6.9% (<52 mmol/mol), had significantly lower Lp(a) levels than patients with poorer metabolic control HbA1c >6.9% (>52 mmol/mol). CONCLUSIONS Lp(a) is a significant risk factor for macrovascular disease, albuminuria and calcified aortic valve disease in patients with type 1 diabetes. Poor metabolic control in patients with type 1 diabetesis associated with increased Lp(a) levels.

By Max Bingham, PhD

With the simple turning of a calendar page, 2020 is upon us, as is the time for the annual New Year message from the editorial committee of Diabetes Care. Each year we highlight the past year’s activities and offer a preview of what lies ahead. An important event in 2019 was the announcement of impact factors for scientific journals. The yearly statement of current impact factors revealed another clear increase for Diabetes Care, from 13.4 to 15.3, placing us among the elite journals in any specialty. We are proud of this ranking and hope for a further increase next year.

The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the “single disease” approach appears untenable, as does the notion of individualizing each single patient’s care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

The impact of dietary fat and protein on postprandial glycemia in type 1 diabetes (T1D) and the need to adjust for them in the mealtime insulin dose have been controversial (1,2). Recently, carefully designed randomized trials in individuals living with T1D have shown protein and fat consumed in meals with carbohydrate reduce the early postprandial rise (1–2 h) and contribute to postprandial hyperglycemia in the late (3–6 h) postprandial period (3–5). In clinical practice, continuous glucose monitoring highlights the glycemic effects of different meal types demonstrating that mealtime insulin dosing strategies based on carbohydrate counting alone have limitations. There is a need for an evidence-based, safe, and practical method to guide insulin adjustments for high-fat, high-protein meals. In this issue of Diabetes Care, Bell et al. (6) address the pressing clinical question of optimal insulin adjustments for meals containing differing amounts of dietary fat. This is important because postprandial hyperglycemia has been identified as a risk factor for the development of long-term complications of diabetes (7), and higher fat diets have increased in popularity in recent years.

Younger age at diagnosis often reflects a greater influence of genetic factors in disease. Type 1 diabetes, which develops most frequently in childhood but can also present in adult life, is a prime candidate to explore the relationships among risk loci, age at diagnosis, and genetic contribution to disease. Type 1 diabetes genetic risk scores (GRS) (calculated as the weighted sum of alleles statistically associated with type 1 diabetes present in a given individual) are inversely correlated with age at diagnosis. Studies have suggested age-related heterogeneity in the association of established risk alleles with type 1 diabetes, although no consistent pattern has developed. Further investigations into the genetic factors that influence age of clinical onset may refine our understanding of type 1 diabetes pathogenesis and provide opportunities for individualized preventive therapies.

The recent development of reliable systems for continuously monitoring interstitial glucose levels has set the stage for a revolution in diabetes research and care. The ability to obtain real-time and summary displays of glycemic patterns of individuals with diabetes, together with rapidly obtained agreement on various definitions and ways of handling the resulting data (1,2), has led to both rapid acceptance of continuous glucose monitoring (CGM) devices and incorporation of CGM into clinical research studies.

Continuous glucose monitoring (CGM) has been demonstrated in randomized trials to improve glucose control in patients with type 1 diabetes (1), but until recently only a minority of participants in the German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registry and the U.S.-based T1D Exchange (T1DX) registry were using CGM (2,3). Over the past decade, both the accuracy and usability of CGM devices have improved considerably with expanded cost coverage of CGM by government statutory and private insurance. Some CGM devices are regulatory body approved for determining insulin dose in most circumstances, thereby reducing the number of fingersticks needed to monitor blood glucose. To assess change in CGM use over time across the age spectrum, we analyzed data from the T1DX and DPV registries for the years 2011, 2013, 2015, and 2017. CGM use (including both real-time and intermittent scanning CGM) at each data collection time point were obtained from clinic medical records. The number of participants with available data on CGM usage varied slightly depending on the calendar year for both registries. In DPV, the cohort size ranged from 17,632 to 21,707 for youth (aged 2 to <18 years) and from 7,651 to 8,390 for adults aged (≥18 years). In T1DX, cohort size ranged from 8,334 to 9,184 …

The majority of youth with type 1 diabetes are above hemoglobin A1c (HbA1c) targets. Continuous glucose monitoring (CGM) has been shown to improve clinical outcomes, and use early in the course of diabetes has the potential to improve glycemic outcomes and improve quality of life. In our clinic, youth with new-onset type 1 diabetes were offered the opportunity to start on CGM (Dexcom G6) soon after diabetes diagnosis. Ongoing CGM coverage was subsequently applied for through the patient’s insurance. Following CGM initiation, youth had a 1-week follow-up with a nurse practitioner. Per clinic standard of care, youth were seen again at 1 month post-diagnosis and every 3 months thereafter. We prospectively collected data on HbA1c, continued CGM use, days of CGM wear, method of viewing CGM data, time in range (TIR), and time in hypoglycemia. Institutional review board approval was obtained for the prospective data collection. From July 2018 to April 2019, we approached 44 youth with newly diagnosed type 1 diabetes to initiate CGM. Forty-one youth (at onset: mean age 9.7 ± 4.1 years, 56% male, 90% with private insurance, 41% non-Hispanic white, HbA1c 12.2 ± 1.8% [110 mmol/mol]) were started on CGM at a mean of 9.0 ± 8.8 days post–diabetes diagnosis (Table 1). Three adolescent youth declined CGM, stating they did …

OBJECTIVE To evaluate glycemia and metrics of glucose variability in youth with type 1 diabetes, and to assess patterns of 24-h glucose variability according to pubertal status. RESEARCH DESIGN AND METHODS Metrics of glycemia, glucose variability, and glucose patterns were assessed by using 4 weeks of continuous glucose monitoring (CGM) data from 107 youth aged 8–17 years with type 1 diabetes for ≥1 year. Glucose values per hour were expressed as percentages relative to the mean glucose over 24 h for a 4-week period. Glucose data were compared on the basis of pubertal status—prepubertal (Tanner stage [T] 1), pubertal (T2–4), and postpubertal (T5)—and A1C categories (<7.5% [<58 mmol/mol], ≥7.5% [≥58 mmol/mol]). RESULTS Youth (50% female, 95% white) had a mean ± SD age of 13.1 ± 2.6 years, diabetes duration of 6.3 ± 3.5 years, and A1C of 7.8 ± 0.8% (62 ± 9 mmol/mol); 88% were pump treated. Prepubertal youth had a higher mean glucose SD (86 ± 12 mg/dL [4.8 ± 0.7 mmol/L]; P = 0.01) and coefficient of variation (CV) (43 ± 5%; P = 0.06) than did pubertal (SD 79 ± 13 mg/dL [4.4 ± 0.7 mmol/L]; CV 41 ± 5%) and postpubertal (SD 77 ± 14 mg/dL [4.3 ± 0.8 mmol/L]; CV 40 ± 5%) youth. Over 24 h, prepubertal youth had the largest excursions from mean glucose and the highest CV across most hours compared with pubertal and postpubertal youth. Across all youth, CV was strongly correlated with the percentage of time with glucose <70 mg/dL (<3.9 mmol/L) ( r = 0.79; P < 0.0001). CONCLUSIONS Prepubertal youth had greater glucose variability independent of A1C than did pubertal and postpubertal youth. A1C alone does not capture the full range of glycemic parameters, highlighting the added insight of CGM in managing youth with type 1 diabetes.

OBJECTIVE We evaluated the safety and efficacy of day-and-night fully closed-loop insulin therapy using faster (Faster-CL) compared with standard insulin aspart (Standard-CL) in young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS In a double-blind, randomized, crossover trial, 20 participants with type 1 diabetes on insulin pump therapy (11 females, aged 21.3 ± 2.3 years, HbA1c 7.5 ± 0.5% [58.5 ± 5.5 mmol/mol]) underwent two 27-h inpatient periods with unannounced afternoon moderate-vigorous exercise and unannounced/uncovered meals. We compared Faster-CL and Standard-CL in random order. During both interventions, the fuzzy-logic control algorithm DreaMed GlucoSitter was used. Glucose sensor data were analyzed by intention-to-treat principle with the difference (between Faster-CL and Standard-CL) in proportion of time in range 70–180 mg/dL (TIR) over 27 h as the primary end point. RESULTS The proportion of TIR was similar for both arms: 53.3% (83% overnight) in Faster-CL and 57.9% (88% overnight) in Standard-CL ( P = 0.170). The proportion of time in hypoglycemia <70 mg/dL was 0.0% for both groups. Baseline-adjusted interstitial prandial glucose increments 1 h after meals were greater in Faster-CL compared with Standard-CL ( P = 0.017). The gaps between measured plasma insulin and estimated insulin-on-board levels at the beginning, at the end, and 2 h after the exercise were smaller in the Standard-CL group ( P = 0.029, P = 0.003, and P = 0.004, respectively). No severe adverse events occurred. CONCLUSIONS Fully closed-loop insulin delivery using either faster or standard insulin aspart was safe and efficient in achieving near-normal glucose concentrations outside postprandial periods. The closed-loop algorithm was better adjusted to the standard insulin aspart.

OBJECTIVE This study assessed the clinical impact of four treatment strategies in adults with type 1 diabetes (T1D): real-time continuous glucose monitoring (rtCGM) with multiple daily insulin injections (rtCGM+MDI), rtCGM with continuous subcutaneous insulin infusion (rtCGM+CSII), self-monitoring of blood glucose with MDI (SMBG+MDI), and SMBG with CSII (SMBG+CSII). RESEARCH DESIGN AND METHODS This 3-year, nonrandomized, prospective, real-world, clinical trial followed 94 participants with T1D (rtCGM+MDI, n = 22; rtCGM+CSII, n = 26; SMBG+MDI, n = 21; SMBG+CSII, n = 25). The main end points were changes in A1C, time in range (70–180 mg/dL [3.9–10 mmol/L]), time below range (<70 mg/dL [<3.9 mmol/L]), glycemic variability, and incidence of hypoglycemia. RESULTS At 3 years, the rtCGM groups (rtCGM+MDI and rtCGM+CSII) had significantly lower A1C (7.0% [53 mmol/mol], P = 0.0002, and 6.9% [52 mmol/mol], P < 0.0001, respectively), compared with the SMBG+CSII and SMBG+MDI groups (7.7% [61 mmol/mol], P = 0.3574, and 8.0% [64 mmol/mol], P = 1.000, respectively), with no significant difference between the rtCGM groups. Significant improvements in percentage of time in range were observed in the rtCGM subgroups (rtCGM+MDI, 48.7–69.0%, P < 0.0001; and rtCGM+CSII, 50.9–72.3%, P < 0.0001) and in the SMBG+CSII group (50.6–57.8%, P = 0.0114). Significant reductions in time below range were found only in the rtCGM subgroups (rtCGM+MDI, 9.4–5.5%, P = 0.0387; and rtCGM+CSII, 9.0–5.3%, P = 0.0235). Seven severe hypoglycemia episodes occurred: SMBG groups, n = 5; sensor-augmented insulin regimen groups, n = 2. CONCLUSIONS rtCGM was superior to SMBG in reducing A1C, hypoglycemia, and other end points in individuals with T1D regardless of their insulin delivery method. rtCGM+MDI can be considered an equivalent but lower-cost alternative to sensor-augmented insulin pump therapy and superior to treatment with SMBG+MDI or SMBG+CSII therapy.

OBJECTIVE The HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of biochemical hypoglycemia without compromising overall glycemic control would restore sufficient hypoglycemia awareness to prevent recurrent severe hypoglycemia in the majority of participants with established type 1 diabetes. Before starting the study, we planned to investigate associations between baseline characteristics and recurrent severe hypoglycemia over 2 years’ follow-up. RESEARCH DESIGN AND METHODS A total of 96 adults with type 1 diabetes and impaired awareness of hypoglycemia participated in a 24-week 2 × 2 factorial randomized controlled trial comparing insulin delivery and glucose monitoring modalities, with the goal of rigorous biochemical hypoglycemia avoidance. The analysis included 71 participants who had experienced severe hypoglycemia in the 12-month prestudy with confirmed absence (complete responder) or presence (incomplete responder) of severe hypoglycemia over 24 months’ follow-up. RESULTS There were 43 (61%) complete responders and 28 (39%) incomplete responders experiencing mean ± SD 1.5 ± 1.0 severe hypoglycemia events/person-year. At 24 months, incomplete responders spent no more time with glucose ≤3 mmol/L (1.4 ± 2.1% vs. 3.0 ± 4.8% for complete responders; P = 0.26), with lower total daily insulin dose (0.45 vs. 0.58 units/24 h; P = 0.01) and greater impairment of hypoglycemia awareness (Clarke score: 3.8 ± 2.2 vs. 2.0 ± 1.9; P = 0.01). Baseline severe hypoglycemia rate (16.9 ± 16.3 vs. 6.4 ± 10.8 events/person-year; P = 0.002) and fear of hypoglycemia were higher in incomplete responders. Peripheral neuropathy was more prevalent in incomplete responders (11 [39%] vs. 2 [4.7%]; P < 0.001) with a trend toward increased autonomic neuropathy. CONCLUSIONS Recurrent severe hypoglycemia was associated with higher preintervention severe hypoglycemia rate, fear of hypoglycemia, and concomitant neuropathy.

OBJECTIVE The inverse relationship between overall glucose control and hypoglycemia risk is weakened by the use of real-time continuous glucose monitoring (rtCGM). We assess the relationship between glucose control and hypoglycemia in people with type 1 diabetes using multiple-dose injection (MDI) regimens, including those at highest risk of hypoglycemia. RESEARCH DESIGN AND METHODS CGM data from the intervention (rtCGM) and control (self-monitored blood glucose [SMBG]) phases of the Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes (DIAMOND) and HypoDE studies were analyzed. The relationship between glucose control (HbA1c and mean rtCGM glucose levels) and percentage time spent in hypoglycemia was explored for thresholds of 3.9 mmol/L (70 mg/dL) and 3.0 mmol/L (54 mg/dL), and ANOVA across the range of HbA1c and mean glucose was performed. RESULTS A nonlinear relationship between mean glucose and hypoglycemia was identified at baseline, with the steepest relationship seen at lower values of mean glucose. The use of rtCGM reduces the exposure to hypoglycemia at all thresholds and flattens the relationship between overall glucose and hypoglycemia, with the most marked impact at lower values of mean glucose and HbA1c. Exposure to hypoglycemia varied at all thresholds across the range of overall glucose at baseline, in the SMBG group, and with rtCGM, but the relationships were weaker in the rtCGM group. CONCLUSIONS Use of rtCGM can flatten and attenuate the relationship between overall glucose control and hypoglycemia, exerting its greatest impact at lower values of HbA1c and mean glucose in people with type 1 diabetes using MDI regimens and at highest risk of hypoglycemia.

OBJECTIVE To estimate real-world off-label use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes, estimate rates of diabetic ketoacidosis (DKA), and compare them with DKA rates observed in sotagliflozin clinical trials. RESEARCH DESIGN AND METHODS We identified initiators of SGLT2 inhibitors in the Sentinel System from March 2013 to June 2018, determined the prevalence of type 1 diabetes using a narrow and a broad definition, and measured rates of DKA using administrative claims data. Standardized incidence ratios (SIRs) were calculated using age- and sex-specific follow-up time in Sentinel and age- and sex-specific DKA rates from sotagliflozin trials 309, 310, and 312. RESULTS Among 475,527 initiators of SGLT2 inhibitors, 0.50% and 0.92% met narrow and broad criteria for type 1 diabetes, respectively. Rates of DKA in the narrow and broad groups were 7.3/100 person-years and 4.5/100 person-years, respectively. Among patients who met narrow criteria for type 1 diabetes, rates of DKA were highest for patients aged 25–44 years, especially females aged 25–44 years (19.7/100 person-years). More DKA events were observed during off-label use of SGLT2 inhibitors in Sentinel than would be expected based on sotagliflozin clinical trials (SIR = 1.83; 95% CI 1.45–2.28). CONCLUSIONS Real-world off-label use of SGLT2 inhibitors among patients with type 1 diabetes accounted for a small proportion of overall SGLT2 inhibitor use. However, the risk for DKA during off-label use was notable, especially among young, female patients. Although real-word rates of DKA exceeded the expectation based on clinical trials, results should be interpreted with caution due to differences in study methods, patient samples, and study drugs.

OBJECTIVE Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345–248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870–135342620) was located in the gene body of CYP2E1 . Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate–adjusted P value threshold of 0.05. CONCLUSIONS Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13 , a gene associated with autism spectrum disorder, and the gene body of CYP2E1 , which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.

OBJECTIVE Vascular complications of diabetes have declined substantially over the past 20 years. However, the impact of modern medical treatments on infectious diseases in people with diabetes remains unknown. RESEARCH DESIGN AND METHODS We estimated rates of infections requiring hospitalizations in adults (≥18 years) with versus without diabetes, using the 2000–2015 National Inpatient Sample and the National Health Interview Surveys. Annual age-standardized and age-specific hospitalization rates in groups with and without diabetes were stratified by infection type. Trends were assessed using Joinpoint regression with the annual percentage change (Δ%/year) reported. RESULTS In 2015, hospitalization rates remained almost four times as high in adults with versus without diabetes (rate ratio 3.8 [95% CI 3.8–3.8]) and as much as 15.7 times as high, depending on infection type. Overall, between 2000 and 2015, rates of hospitalizations increased from 63.1 to 68.7 per 1,000 persons in adults with diabetes and from 15.5 to 16.3 in adults without diabetes. However, from 2008, rates declined 7.9% in adults without diabetes (from 17.7 to 16.3 per 1,000 persons; Δ%/year −1.5, P < 0.01), while no significant decline was noted in adults with diabetes. The lack of decline in adults with diabetes in the later period was driven by significant increases in rates of foot infections and cellulitis as well as by lack of decline for pneumonia and postoperative wound infections in young adults with diabetes. CONCLUSIONS Findings from this study highlight the need for greater infectious risk mitigation in adults with diabetes, especially young adults with diabetes.

OBJECTIVE We examined trends in diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes at a large pediatric diabetes center between 2010 and 2017, overlapping with the Affordable Care Act’s overhaul of U.S. health care. RESEARCH DESIGN AND METHODS Colorado residents <18 years old who were diagnosed with type 1 diabetes from 2010 to 2017 and subsequently followed at the Barbara Davis Center for Diabetes were included. Logistic regression models were used to test associations among age, sex, race/ethnicity, insurance, language, year of diagnosis, and rural/nonrural residence and DKA at diagnosis. Linear regression models were used to test the association of each predictor with HbA1c at diagnosis. RESULTS There were 2,429 subjects who met the inclusion criteria. From 2010 to 2017, the rate of DKA increased from 41 to 58%. It increased from 35.3 to 59.6% among patients with private insurance (odds ratio 1.10 [95% CI 1.05–1.15]; P < 0.0001) but remained unchanged (52.2–58.8%) among children with public insurance (1.03 [0.97–1.09]; P = 0.36). In the multivariable model, public insurance (1.33 [1.08–1.64]; P = 0.007), rural address (1.42 [1.08–1.86]; P = 0.013), and HbA1c (1.32 [1.26–1.38]; P < 0.0001) were positively associated with DKA, whereas age, race/ethnicity, sex, and primary language were not. CONCLUSIONS The increase in the rate of DKA in patients with newly diagnosed type 1 diabetes was driven by patients with private insurance. This paradoxically occurred during a time of increasing health insurance coverage. More study is needed to understand the factors driving these changes.

OBJECTIVE We aimed to investigate the rate of progression of nonalbuminuric chronic kidney disease (CKD) to end-stage kidney disease (ESKD) or death or major cardiovascular events (MACE) compared with albuminuric and nonalbuminuric phenotypes. RESEARCH DESIGN AND METHODS We included 10,185 participants with type 2 diabetes enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Based on baseline albuminuria and estimated glomerular filtration rate (eGFR), participants were classified as having no kidney disease (no CKD), albuminuria only (albuminuric non-CKD), reduced eGFR only (nonalbuminuric CKD), or both albuminuria and reduced eGFR (albuminuric CKD). The rate of eGFR decline and hazard ratios (HRs) for ESKD or death or MACE were calculated. RESULTS For individuals with no CKD and those with nonalbuminuric CKD, the rates of eGFR decline were −1.31 and −0.60 mL/min/year, respectively ( P < 0.001). In competing-risks analysis (no CKD as the reference), HRs for ESKD indicated no increased risk for nonalbuminuric CKD (0.76 [95% CI 0.34, 1.70]) and greatest risk for albuminuric CKD (4.52 [2.91, 7.01]). In adjusted Cox models, HRs for death and MACE were highest for albumuniuric CKD (2.38 [1.92, 2.90] and 2.37 [1.89, 2.97], respectively) and were higher for albuminuric non-CKD (1.82 [1.59, 2.08] and 1.88 [1.63, 2.16], respectively) than for those with nonalbuminuric CKD (1.42 [1.14, 1.78] and 1.44 [1.13, 1.84], respectively). CONCLUSIONS Those with nonalbuminuric CKD showed a slower rate of decline in eGFR than did any other group; however, these individuals still carry a greater risk for death and MACE than do those with no CKD.

OBJECTIVE Oxidative stress is believed to play an important role in the pathophysiology of type 2 diabetes, but the few cohort studies that have assessed the association of oxidative stress biomarkers with type 2 diabetes incidence were small and reported inconclusive results. RESEARCH DESIGN AND METHODS We examined the associations of urinary oxidized guanine/guanosine (OxGua) levels (a biomarker of DNA/RNA oxidation) and urinary 8-isoprostane levels (a biomarker of lipid peroxidation) with type 2 diabetes incidence in 7,828 individuals initially without diabetes from a population-based German cohort study with 14 years of follow-up. Hazard ratios (HRs) (95% CIs) per 1 SD were obtained using multivariable-adjusted Cox proportional hazards regression models. RESULTS In the total population, weak but statistically significant associations with type 2 diabetes incidence were observed for OxGua levels (HR [95% CI] per 1 SD 1.05 [1.01; 1.09]) and 8-isoprostane levels (1.04 [1.00; 1.09]). Stratified analyses showed that associations of both biomarkers with type 2 diabetes incidence were absent in the youngest age-group (50–59 years) and strongest in the oldest age-group (65–75 years) of the cohort, with HR of OxGua levels 1.14 (1.05; 1.23) per 1 SD and of 8-isoprostane levels 1.22 (1.02; 1.45) per 1 SD. CONCLUSIONS These results from a large cohort study support suggestions that an imbalanced redox system contributes to the development of type 2 diabetes but suggest that this association becomes clinically apparent at older ages only, possibly as a result of reduced cellular repair capacity.

OBJECTIVE We aimed to assess whether individuals with type 2 diabetes (T2D) have increased risk of vertebral fractures (VFs) and to estimate nonvertebral fracture and mortality risk among individuals with both prevalent T2D and VFs. RESEARCH DESIGN AND METHODS A systematic PubMed search was performed to identify studies that investigated the relationship between T2D and VFs. Cohorts providing individual participant data (IPD) were also included. Estimates from published summary data and IPD cohorts were pooled in a random-effects meta-analysis. Multivariate Cox regression models were used to estimate nonvertebral fracture and mortality risk among individuals with T2D and VFs. RESULTS Across 15 studies comprising 852,705 men and women, individuals with T2D had lower risk of prevalent (odds ratio [OR] 0.84 [95% CI 0.74–0.95]; I 2 = 0.0%; P het = 0.54) but increased risk of incident VFs (OR 1.35 [95% CI 1.27–1.44]; I 2 = 0.6%; P het = 0.43). In the IPD cohorts ( N = 19,820), risk of nonvertebral fractures was higher in those with both T2D and VFs compared with those without T2D or VFs (hazard ratio [HR] 2.42 [95% CI 1.86–3.15]) or with VFs (HR 1.73 [95% CI 1.32–2.27]) or T2D (HR 1.94 [95% CI 1.46–2.59]) alone. Individuals with both T2D and VFs had increased mortality compared with individuals without T2D and VFs (HR 2.11 [95% CI 1.72–2.59]) or with VFs alone (HR 1.84 [95% CI 1.49–2.28]) and borderline increased compared with individuals with T2D alone (HR 1.23 [95% CI 0.99–1.52]). CONCLUSIONS Based on our findings, individuals with T2D should be systematically assessed for presence of VFs, and, as in individuals without T2D, their presence constitutes an indication to start osteoporosis treatment for the prevention of future fractures.

OBJECTIVE The relationship between acute pancreatitis and incident diabetes is unclear. We assessed whether a resolved single event of acute pancreatitis in childhood was associated with incident diabetes in adulthood. RESEARCH DESIGN AND METHODS A nationwide, population-based study of 1,802,110 Israeli adolescents (mean age 17.4 years [range 16–20]) who were examined before compulsory military service between 1979 and 2008 and whose data were linked to the Israeli National Diabetes Registry (INDR). Resolved pancreatitis was defined as a history of a single event of acute pancreatitis with normal pancreatic function at enrollment. Logistic regression analysis was applied. RESULTS Incident diabetes developed in 4.6% of subjects with resolved pancreatitis (13 of 281; none of these cases were identified as type 1 diabetes) and 2.5% among the unexposed group (44,463 of 1,801,716). Resolved acute pancreatitis was associated with incident diabetes with an odds ratio (OR) of 2.23 (95% CI 1.25–3.98) with adjustment for age, sex, and birth year. Findings persisted after further adjustments for baseline BMI and sociodemographic confounders (OR 2.10 [95% CI 1.15–3.84]). Childhood pancreatitis was associated with a diagnosis of diabetes at a younger age, with 92% of diabetes case subjects diagnosed before 40 years of age compared with 47% in the unexposed group ( P = 0.002). The association accentuated when the study sample was limited to individuals of unimpaired health or normal BMI at baseline. CONCLUSIONS A history of acute pancreatitis in childhood with normal pancreatic function in late adolescence is a risk factor for incident type 2 diabetes, especially at young adulthood.

OBJECTIVE To assess weight and HbA1c changes in the Healthier You: National Health Service Diabetes Prevention Programme (NHS DPP), the largest DPP globally to achieve universal population coverage. RESEARCH DESIGN AND METHODS A service evaluation assessed intervention effectiveness for adults with nondiabetic hyperglycemia (HbA1c 42–47 mmol/mol [6.0–6.4%] or fasting plasma glucose 5.5–6.9 mmol/L) between program launch in June 2016 and December 2018, using prospectively collected, national service–level data in England. RESULTS By December 2018, 324,699 people had been referred, 152,294 had attended the initial assessment, and 96,442 had attended at least 1 of 13 group-based intervention sessions. Allowing sufficient time to elapse, 53% attended an initial assessment, 36% attended at least one group-based session, and 19% completed the intervention (attended >60% of sessions). Of the 32,665 who attended at least one intervention session and had sufficient time to finish, 17,252 (53%) completed: intention-to-treat analyses demonstrated a mean weight loss of 2.3 kg (95% CI 2.2, 2.3) and an HbA1c reduction of 1.26 mmol/mol (1.20, 1.31) (0.12% [0.11, 0.12]); completer analysis demonstrated a mean weight loss of 3.3 kg (3.2, 3.4) and an HbA1c reduction of 2.04 mmol/mol (1.96, 2.12) (0.19% [0.18, 0.19]). Younger age, female sex, Asian and black ethnicity, lower socioeconomic status, and normal baseline BMI were associated with less weight loss. Older age, female sex, black ethnicity, lower socioeconomic status, and baseline overweight and obesity were associated with a smaller HbA1c reduction. CONCLUSIONS Reductions in weight and HbA1c compare favorably with those reported in recent meta-analyses of pragmatic studies and suggest likely future reductions in participant type 2 diabetes incidence.

OBJECTIVE Evaluate the safety and efficacy of RVT-1502, a novel oral glucagon receptor antagonist, in subjects with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS In a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes ( n = 166) on a stable dose of metformin were randomized (1:1:1:1) to placebo or RVT-1502 5, 10, or 15 mg once daily for 12 weeks. The primary end point was change from baseline in HbA1c for each dose of RVT-1502 compared with placebo. Secondary end points included change from baseline in fasting plasma glucose (FPG) and safety assessments. RESULTS Over 12 weeks, RVT-1502 significantly reduced HbA1c relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups ( P < 0.001), respectively, and FPG decreased by 2.1, 2.2, and 2.6 mmol/L ( P < 0.001). The proportions of subjects achieving an HbA1c <7.0% were 19.5%, 39.5%, 39.5%, and 45.0% with placebo and RVT-1502 5, 10, and 15 mg ( P ≤ 0.02 vs. placebo). The frequency of hypoglycemia was low, and no episodes were severe. Mild increases in mean aminotransferase levels remaining below the upper limit of normal were observed with RVT-1502 but were reversible and did not appear to be dose related, with no other liver parameter changes. Weight and lipid changes were similar between RVT-1502 and placebo. RVT-1502–associated mild increases in blood pressure were not dose related or consistent across time. CONCLUSIONS Glucagon receptor antagonism with RVT-1502 significantly lowers HbA1c and FPG, with a safety profile that supports further clinical development with longer-duration studies ([NCT02851849][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02851849&atom=%2Fdiacare%2F43%2F1%2F161.atom

OBJECTIVE Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at <7 years (<7 group) and those diagnosed at age ≥13 years (≥13 group), with both B- and T-lymphocyte islet inflammation common in children in the <7 group, whereas B cells are rare in the ≥13 group. Based on these observations, we sought to identify differences in genetic susceptibility between these prespecified age-at-diagnosis groups to inform on the etiology of the most aggressive form of type 1 diabetes that initiates in the first years of life. RESEARCH DESIGN AND METHODS Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA and 55 non-HLA loci) had significantly stronger effect sizes in the <7 group compared with the ≥13 group, using genotype data from 27,071 individuals (18,485 control subjects and 3,121 case subjects diagnosed at <7 years, 3,757 at 7–13 years, and 1,708 at ≥13 years). RESULTS Six HLA haplotypes/classical alleles and six non-HLA regions, one of which functions specifically in β-cells ( GLIS3 ) and the other five likely affecting key T-cell ( IL2RA , IL10 , IKZF3 , and THEMIS ), thymus ( THEMIS ), and B-cell development/functions ( IKZF3 and IL10 ) or in both immune and β-cells ( CTSH ), showed evidence for stronger effects in the <7 group. CONCLUSIONS A subset of type 1 diabetes–associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic β- and immune cells.

OBJECTIVE A subset of people with long-standing type 1 diabetes (T1D) appears to be protected from microvascular and macrovascular complications. Previous studies have focused on improved abilities to respond to glucose and its downstream effects as protective mechanisms. It is unclear whether lipoproteins play a role in the vascular health of these people. We therefore determined whether HDL particle concentration, size, function, and/or protein composition associate with protection from vascular complications. RESEARCH DESIGN AND METHODS We studied two independent cross-sectional cohorts with T1D: the T1D Exchange Living Biobank ( n = 47) and the Joslin Medalist Study ( n = 100). Some of the subjects had vascular complications, whereas others never exhibited vascular complications, despite an average duration of diabetes in the cohorts of 45 years. We assessed HDL particle size and concentration by calibrated ion mobility analysis, the HDL proteome by targeted mass spectrometry, and HDL function ex vivo by quantifying cholesterol efflux capacity and inhibition of monocyte adhesion to endothelial cells. RESULTS In both cohorts, people without vascular complications exhibited significantly higher concentrations of medium-sized HDL particles (M-HDL) independently of total and HDL cholesterol levels. While no consistent differences in HDL functions were observed ex vivo, people without vascular complications had higher levels of HDL-associated paraoxonase 1 (PON1), an enzyme that inhibits atherosclerosis in animal models. CONCLUSIONS Elevated concentrations of M-HDL particles and elevated levels of HDL-associated PON1 may contribute to long-term protection from the vascular complications of diabetes by pathways that are independent of total cholesterol and HDL cholesterol.

OBJECTIVE To compare diabetic kidney disease (DKD) rates over 5 years of follow-up in two cohorts of severely obese adolescents with type 2 diabetes (T2D) undergoing medical or surgical treatment for T2D. RESEARCH DESIGN AND METHODS A secondary analysis was performed of data collected from obese participants of similar age and racial distribution enrolled in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and the Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) studies. Teen-LABS participants underwent metabolic bariatric surgery (MBS). TODAY participants were randomized to metformin alone or in combination with rosiglitazone or intensive lifestyle intervention, with insulin therapy given for glycemic progression. Glycemic control, BMI, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), and prevalence of hyperfiltration (eGFR ≥135 mL/min/1.73 m2) and elevated UAE (≥30 mg/g) were assessed annually. RESULTS Participants with T2D from Teen-LABS ( n = 30, mean ± SD age, 16.9 ± 1.3 years; 70% female; 60% white; BMI 54.4 ± 9.5 kg/m2) and TODAY ( n = 63, age 15.3 ± 1.3 years; 56% female; 71% white; BMI 40.5 ± 4.9 kg/m2) were compared. During 5 years of follow-up, hyperfiltration decreased from 21% to 18% in Teen-LABS and increased from 7% to 48% in TODAY. Elevated UAE decreased from 27% to 5% in Teen-LABS and increased from 21% to 43% in TODAY. Adjusting for baseline age, sex, BMI, and HbA1c, TODAY participants had a greater odds of hyperfiltration (odds ratio 15.7 [95% CI 2.6, 94.3]) and elevated UAE (27.3 [4.9, 149.9]) at 5 years of follow-up. CONCLUSIONS Compared with MBS, medical treatment of obese youth with T2D was associated with a higher odds of DKD over 5 years.

OBJECTIVE Diabetes increases the risk of all-cause mortality and sudden cardiac death (SCD). The exact mechanisms leading to sudden death in diabetes are not well known. We compared the incidence of appropriate shocks and mortality in patients with versus without diabetes with a prophylactic implantable cardioverter defibrillator (ICD) included in the retrospective EU-CERT-ICD registry. RESEARCH DESIGN AND METHODS AND RESULTS A total of 3,535 patients from 12 European EU-CERT-ICD centers with a mean age of 63.7 ± 11.2 years (82% males) at the time of ICD implantation were included in the analysis. A total of 995 patients (28%) had a history of diabetes. All patients had an ICD implanted for primary SCD prevention. End points were appropriate shock and all-cause mortality. Mean follow-up time was 3.2 ± 2.3 years. Diabetes was associated with a lower risk of appropriate shocks (adjusted hazard ratio [HR] 0.77 [95% CI 0.62–0.96], P = 0.02). However, patients with diabetes had significantly higher mortality (adjusted HR 1.30 [95% CI 1.11–1.53], P = 0.001). CONCLUSIONS All-cause mortality is higher in patients with diabetes than in patients without diabetes with primary prophylactic ICDs. Subsequently, patients with diabetes have a lower incidence of appropriate ICD shocks, indicating that the excess mortality might not be caused primarily by ventricular tachyarrhythmias. These findings suggest a limitation of the potential of prophylactic ICD therapy to improve survival in patients with diabetes with impaired left ventricular function.

OBJECTIVE Prediabetes and type 2 diabetes are associated with structural brain abnormalities, often observed in cognitive disorders. Besides visible lesions, (pre)diabetes might also be associated with alterations of the intrinsic organization of the white matter. In this population-based cohort study, the association of prediabetes and type 2 diabetes with white matter network organization was assessed. RESEARCH DESIGN AND METHODS In the Maastricht Study, a type 2 diabetes–enriched population-based cohort study (1,361 subjects with normal glucose metabolism, 348 with prediabetes, and 510 with type 2 diabetes assessed by oral glucose tolerance test; 52% men; aged 59 ± 8 years), 3 Tesla structural and diffusion MRI was performed. Whole-brain white matter tractography was used to assess the number of connections (node degree) between 94 brain regions and the topology (graph measures). Multivariable linear regression analyses were used to investigate the associations of glucose metabolism status with network measures. Associations were adjusted for age, sex, education, and cardiovascular risk factors. RESULTS Prediabetes and type 2 diabetes were associated with lower node degree after full adjustment (standardized [st]βPrediabetes = −0.055 [95% CI −0.172, 0.062], stβType2diabetes = −0.256 [−0.379, −0.133], P trend < 0.001). Prediabetes was associated with lower local efficiency (stβ = −0.084 [95% CI −0.159, −0.008], P = 0.033) and lower clustering coefficient (stβ = −0.097 [95% CI −0.189, −0.005], P = 0.049), whereas type 2 diabetes was not. Type 2 diabetes was associated with higher communicability (stβ = 0.148 [95% CI 0.042, 0.253], P = 0.008). CONCLUSIONS These findings indicate that prediabetes and type 2 diabetes are associated with fewer white matter connections and weaker organization of white matter networks. Type 2 diabetes was associated with higher communicability, which was not yet observed in prediabetes and may reflect the use of alternative white matter connections.

OBJECTIVE Long before clinical complications of type 1 diabetes (T1D) develop, oxygen supply and use can be altered during activities of daily life. We examined in patients with uncomplicated T1D all steps of the oxygen pathway, from the lungs to the mitochondria, using an integrative ex vivo (muscle biopsies) and in vivo (during exercise) approach. RESEARCH DESIGN AND METHODS We compared 16 adults with T1D with 16 strictly matched healthy control subjects. We assessed lung diffusion capacity for carbon monoxide and nitric oxide, exercise-induced changes in arterial O2 content (SaO2, PaO2, hemoglobin), muscle blood volume, and O2 extraction (via near-infrared spectroscopy). We analyzed blood samples for metabolic and hormonal vasoactive moieties and factors that are able to shift the O2-hemoglobin dissociation curve. Mitochondrial oxidative capacities were assessed in permeabilized vastus lateralis muscle fibers. RESULTS Lung diffusion capacity and arterial O2 transport were normal in patients with T1D. However, those patients displayed blunted exercise-induced increases in muscle blood volume, despite higher serum insulin, and in O2 extraction, despite higher erythrocyte 2,3-diphosphoglycerate. Although complex I– and complex II–supported mitochondrial respirations were unaltered, complex IV capacity (relative to complex I capacity) was impaired in patients with T1D, and this was even more apparent in those with long-standing diabetes and high HbA1c. ![Graphic][1]O2max was lower in patients with T1D than in the control subjects. CONCLUSIONS Early defects in microvascular delivery of blood to skeletal muscle and in complex IV capacity in the mitochondrial respiratory chain may negatively impact aerobic fitness. These findings are clinically relevant considering the main role of skeletal muscle oxidation in whole-body glucose disposal. [1]: /embed/inline-graphic-1.gif

OBJECTIVE To evaluate the prognostic importance of resistant hypertension (RHT) for the development of complications in a cohort of individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 646 patients had the diagnosis of apparent treatment-resistant hypertension (aRHT) based on mean office blood pressure (BP) levels during the 1st year of follow-up. They were reclassified as white-coat/controlled or true/uncontrolled RHT according to 24-h ambulatory BP monitoring (ABPM), using the traditional BP cutoffs and the new 2017 American College of Cardiology (ACC)/American Heart Association (AHA) criteria. Multivariate Cox analyses examined the associations between RHT diagnoses and the occurrence of microvascular and cardiovascular complications and all-cause and cardiovascular mortality. RESULTS During a median follow-up of 10 years, 177 patients had a cardiovascular event (145 major ones); 222 patients died (101 from cardiovascular diseases); 200 had a renal event; 156 had a retinopathy event; and 174 patients had a neuropathy event. In relation to non-RHT individuals, aRHT (present in 44.6% and 50% by the traditional and new criteria, respectively) predicted all cardiovascular and mortality outcomes, with hazard ratios (HRs) between 1.64 and 2.16, but none of the microvascular outcomes. True RHT increased the HRs (from 1.81 to 2.25) and additionally predicted renal outcomes. White-coat/controlled RHT implied an increased risk (HRs 1.33–1.86) that was intermediate between non-RHT and true RHT individuals. Classifications using the traditional and the new ACC/AHA criteria were equivalent. CONCLUSIONS In patients with type 2 diabetes, the presence of aRHT implied an increased risk of cardiovascular and mortality outcomes, and classification based on ABPM predicted renal outcomes and improved cardiovascular/mortality risk stratification.

OBJECTIVE Impaired insulin sensitivity is associated with hyperfiltration (i.e., elevated glomerular filtration rate [GFR]) in adolescents with type 2 diabetes (T2D) and adults with prediabetes. Yet, these relationships are based on studies that relied on estimated GFR (eGFR), estimates of insulin sensitivity, or both. We aimed to verify the relationship between insulin sensitivity and renal hemodynamic function by gold standard methods in adults with T2D. RESEARCH DESIGN AND METHODS Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp (M value) (glucose infusion rate in mg/kglean/min) and renal hemodynamic function by urinary inulin (GFR) and para-aminohippuric acid (effective renal plasma flow [ERPF]) clearances in participants with T2D without overt kidney disease. Filtration fraction (FF) (GFR/ERPF) was calculated. Relationships between insulin sensitivity and renal hemodynamic parameters were examined by multivariable linear regression. Renal hemodynamic parameters were examined across tertiles of M values. RESULTS We tested 44 adults with T2D, of whom 77% were male, with mean ± SD age 63 ± 7 years, BMI 31.2 ± 4.0 kg/m2, and HbA1c 7.4 ± 0.6%. Average GFR was 110 ± 26 mL/min, with an FF of 22.1 ± 2.8% and median 24-h urinary albumin excretion of 11.3 mg (interquartile range 5.8–17.0). Average M value was 5.6 ± 2.9 mg/kglean/min. Insulin sensitivity inversely correlated with GFR ( r = −0.44, P < 0.01) and FF ( r = −0.40, P < 0.01), and these associations remained significant after multivariable adjustments for age, sex, renin-angiotensin system inhibitor use, and HbA1c. In addition, GFR, FF, and urinary albumin excretion were highest in the participants in the lowest M value tertile. CONCLUSIONS For the first time, we demonstrate that impaired insulin sensitivity is associated with intrarenal hemodynamic dysfunction by gold standard techniques in adults with T2D treated with metformin monotherapy.

OBJECTIVE Poor sleep has been identified as a risk factor for poor glycemic control in individuals with type 2 diabetes (T2D). As optimal sleep can be characterized in several ways, we evaluated which sleep characteristics are most strongly associated with glycated hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS A total of 172 patients with T2D completed 7-day wrist-actigraphy and sleep questionnaires. Linear regression was used to evaluate associations between sleep measures (total sleep duration, variability in sleep duration, midsleep time, variability in midsleep time, sleep efficiency, subjective sleep quality, and subjective insomnia symptoms) and HbA1c, individually and in concert. RESULTS Variability in sleep duration was individually most strongly associated with HbA1c (β = 0.239; P = 0.002; R 2 = 4.9%), followed by total sleep duration (U-shaped: β = 1.161/β2 = 1.044; P = 0.017/0.032; R 2 = 4.3%), subjective sleep quality (β = 0.191; P = 0.012; R 2 = 3.6%), variability in midsleep time (β = 0.184; P = 0.016; R 2 = 3.4%), and sleep efficiency (β = −0.150; R 2 = 2.3%). Midsleep time and subjective insomnia symptoms were not associated with HbA1c. In combination, variability in sleep duration, total sleep duration, and subjective sleep quality were significantly associated with HbA1c, together explaining 10.3% of the variance in HbA1c. Analyses adjusted for covariates provided similar results, although the strength of associations was generally decreased and showing total sleep duration and subjective sleep quality to be most strongly associated with HbA1c, together explaining 6.0% of the variance in HbA1c. CONCLUSIONS Sleep in general may be a modifiable factor of importance for patients with T2D. The prevention of sleep curtailment may serve as a primary focus in the sleep-centered management of T2D.

OBJECTIVE In 2016, the U.S. Food and Drug Administration (FDA) revised metformin’s label to permit use in patients with mild-moderate chronic kidney disease. We sought to determine whether this change was associated with increased reports of metformin-associated lactic acidosis (MALA) to the FDA’s Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS Publicly available FAERS reports were analyzed. RESULTS MALA reports increased from 521 in 2015 to 1,939 in 2018. After restriction to U.S. reports, absolute and relative increase in MALA reports was less, from 111 to 243. The proportionate reporting ratio (PRR), a measure adjusted for rates of other adverse event reports, was stable. CONCLUSIONS The increased reports deserve attention, but the PRR’s stability and FAERS’s known limitations, including lack of a denominator or control group, do not permit the conclusion that U.S. MALA rates have increased. Further study with more robust data sources is needed.