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Intrahepatic Fat and Postprandial Glycemia Increase After Consumption of a Diet Enriched in Saturated Fat Compared With Free Sugars

OBJECTIVE

Debate continues regarding the influence of dietary fats and sugars on the risk of developing metabolic diseases, including insulin resistance and nonalcoholic fatty liver disease (NAFLD). We investigated the effect of two eucaloric diets, one enriched with saturated fat (SFA) and the other enriched with free sugars (SUGAR), on intrahepatic triacylglycerol (IHTAG) content, hepatic de novo lipogenesis (DNL), and whole-body postprandial metabolism in overweight males.

RESEARCH DESIGN AND METHODS

Sixteen overweight males were randomized to consume the SFA or SUGAR diet for 4 weeks before consuming the alternate diet after a 7-week washout period. The metabolic effects of the respective diets on IHTAG content, hepatic DNL, and whole-body metabolism were investigated using imaging techniques and metabolic substrates labeled with stable-isotope tracers.

RESULTS

Consumption of the SFA diet significantly increased IHTAG by mean ± SEM 39.0 ± 10.0%, while after the SUGAR diet IHTAG was virtually unchanged. Consumption of the SFA diet induced an exaggerated postprandial glucose and insulin response to a standardized test meal compared with SUGAR. Although whole-body fat oxidation, lipolysis, and DNL were similar following the two diets, consumption of the SUGAR diet resulted in significant (P < 0.05) decreases in plasma total, HDL, and non-HDL cholesterol and fasting β-hydroxybutyrate plasma concentrations.

CONCLUSIONS

Consumption of an SFA diet had a potent effect, increasing IHTAG together with exaggerating postprandial glycemia. The SUGAR diet did not influence IHTAG and induced minor metabolic changes. Our findings indicate that a diet enriched in SFA is more harmful to metabolic health than a diet enriched in free sugars.




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Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study

OBJECTIVE

Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV.

RESEARCH DESIGN AND METHODS

In the population-based Maastricht Study (n = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [n = 1,226], prediabetes [n = 331], and type 2 diabetes [n = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual z-scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors.

RESULTS

After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: –0.15 [–0.27; –0.03] and –0.34 [–0.46; –0.22], respectively, P for trend <0.001; for frequency domain: –0.14 [–0.26; –0.02] and –0.31 [–0.43; –0.19], respectively, P for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: –0.16 [–0.21; –0.12], –0.16 [–0.21; –0.12], and –0.15 [–0.20; –0.10], respectively; frequency domain: –0.14 [–0.19; –0.10], –0.14 [–0.18; –0.09], and –0.13 [–0.18; –0.08], respectively).

CONCLUSIONS

Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes.




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Underweight Increases the Risk of End-Stage Renal Diseases for Type 2 Diabetes in Korean Population: Data From the National Health Insurance Service Health Checkups 2009-2017

OBJECTIVE

There is a controversy over the association between obesity and end-stage renal disease (ESRD) in people with or without type 2 diabetes; therefore, we examined the effect of BMI on the risk of ESRD according to glycemic status in the Korean population.

RESEARCH DESIGN AND METHODS

The study monitored 9,969,848 participants who underwent a National Health Insurance Service health checkup in 2009 from baseline to the date of diagnosis of ESRD during a follow-up period of ~8.2 years. Obesity was categorized by World Health Organization recommendations for Asian populations, and glycemic status was categorized into the following five groups: normal, impaired fasting glucose (IFG), newly diagnosed diabetes, diabetes <5 years, and diabetes ≥5 years.

RESULTS

Underweight was associated with a higher risk of ESRD in all participants after adjustment for all covariates. In the groups with IFG, newly diagnosed type 2 diabetes, diabetes duration <5 years, and diabetes ≥5 years, the hazard ratio (HR) of the underweight group increased with worsening glycemic status (HR 1.431 for IFG, 2.114 for newly diagnosed diabetes, 4.351 for diabetes <5 years, and 6.397 for diabetes ≥5 years), using normal weight with normal fasting glucose as a reference. The adjusted HRs for ESRD were also the highest in the sustained underweight group regardless of the presence of type 2 diabetes (HR 1.606 for nondiabetes and 2.14 for diabetes).

CONCLUSIONS

Underweight showed more increased HR of ESRD according to glycemic status and diabetes duration in the Korean population. These associations also persisted in the group with sustained BMI during the study period.




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Diabetes, Cognitive Decline, and Mild Cognitive Impairment Among Diverse Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging Results (HCHS/SOL)

OBJECTIVE

Hispanics/Latinos are the largest ethnic/racial group in the U.S., have the highest prevalence of diabetes, and are at increased risk for neurodegenerative disorders. Currently, little is known about the relationship between diabetes and cognitive decline and disorders among diverse Hispanics/Latinos. The purpose of this study is to clarify these relationships in diverse middle-aged and older Hispanics/Latinos.

RESEARCH DESIGN AND METHODS

The Study of Latinos–Investigation of Neurocognitive Aging (SOL-INCA) is an ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). HCHS/SOL is a multisite (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA), probability-sampled (i.e., representative of targeted populations), and prospective cohort study. Between 2016 and 2018, SOL-INCA enrolled diverse Hispanics/Latinos aged ≥50 years (n = 6,377). Global cognitive decline and mild cognitive impairment (MCI) were the primary outcomes.

RESULTS

Prevalent diabetes at visit 1, but not incident diabetes at visit 2, was associated with significantly steeper global cognitive decline (βGC = –0.16 [95% CI –0.25; –0.07]; P < 0.001), domain-specific cognitive decline, and higher odds of MCI (odds ratio 1.74 [95% CI 1.34; 2.26]; P < 0.001) compared with no diabetes in age- and sex-adjusted models.

CONCLUSIONS

Diabetes was associated with cognitive decline and increased MCI prevalence among diverse Hispanics/Latinos, primarily among those with prevalent diabetes at visit 1. Our findings suggest that significant cognitive decline and MCI may be considered additional disease complications of diabetes among diverse middle-aged and older Hispanics/Latinos.




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The Prognosis of Patients With Type 2 Diabetes and Nonalbuminuric Diabetic Kidney Disease Is Not Always Poor: Implication of the Effects of Coexisting Macrovascular Complications (JDDM 54)

OBJECTIVE

Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes.

RESEARCH DESIGN AND METHODS

A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m2) at baseline, participants were classified into the four DKD phenotypes—no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR—to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline.

RESULTS

During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher.

CONCLUSIONS

Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.




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The Impact of Medicaid Expansion on Diabetes Management

OBJECTIVE

Diabetes is a chronic health condition contributing to a substantial burden of disease. According to the Robert Wood Johnson Foundation, 10.9 million people were newly insured by Medicaid between 2013 and 2016. Considering this coverage expansion, the Affordable Care Act (ACA) could significantly affect people with diabetes in their management of the disease. This study evaluates the impact of the Medicaid expansion under the ACA on diabetes management.

RESEARCH DESIGN AND METHODS

This study includes 22,335 individuals with diagnosed diabetes from the 2011 to 2016 Behavioral Risk Factor Surveillance System. It uses a difference-in-differences approach to evaluate the impact of the Medicaid expansion on self-reported access to health care, self-reported diabetes management, and self-reported health status. Additionally, it performs a triple-differences analysis to compare the impact between Medicaid expansion and nonexpansion states considering diabetes rates of the states.

RESULTS

Significant improvements in Medicaid expansion states as compared with non–Medicaid expansion states were evident in self-reported access to health care (0.09 score; P = 0.023), diabetes management (1.91 score; P = 0.001), and health status (0.10 score; P = 0.026). Among states with large populations with diabetes, states that expanded Medicaid reported substantial improvements in these areas in comparison with those that did not expand.

CONCLUSIONS

The Medicaid expansion has significant positive effects on self-reported diabetes management. While states with large diabetes populations that expanded Medicaid have experienced substantial improvements in self-reported diabetes management, non–Medicaid expansion states with high diabetes rates may be facing health inequalities. The findings provide policy implications for the diabetes care community and policy makers.




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Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial

OBJECTIVE

Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population.

RESEARCH DESIGN AND METHODS

Satiety and Clinical Adiposity—Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ≤2 oral antidiabetic drugs.

RESULTS

Individuals were randomized to liraglutide 3.0 mg (n = 198) or placebo (n = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was –5.8% for liraglutide 3.0 mg versus –1.5% with placebo (estimated treatment difference –4.3% [95% CI –5.5; –3.2]; P < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ≥5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; P < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA1c and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed.

CONCLUSIONS

In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.




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Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease

OBJECTIVE

Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome.

RESEARCH DESIGN AND METHODS

In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4–12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random).

RESULTS

At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68–0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes.

CONCLUSIONS

In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.




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Medication Adherence During Adjunct Therapy With Statins and ACE Inhibitors in Adolescents With Type 1 Diabetes

OBJECTIVE

Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

There were 443 adolescents with type 1 diabetes recruited into the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and exposed to treatment with two oral drugs—an ACE inhibitor and a statin—as well as combinations of both or placebo for 2–4 years. Adherence was assessed every 3 months with the Medication Event Monitoring System (MEMS) and pill count.

RESULTS

Median adherence during the trial was 80.2% (interquartile range 63.6–91.8) based on MEMS and 85.7% (72.4–92.9) for pill count. Adherence based on MEMS and pill count dropped from 92.9% and 96.3%, respectively, at the first visit to 76.3% and 79.0% at the end of the trial. The percentage of study participants with adherence ≥75% declined from 84% to 53%. A good correlation was found between adherence based on MEMS and pill count (r = 0.82, P < 0.001). Factors associated with adherence were age, glycemic control, and country.

CONCLUSIONS

We report an overall good adherence to ACE inhibitors and statins during a clinical trial, although there was a clear decline in adherence over time. Older age and suboptimal glycemic control at baseline predicted lower adherence during the trial, and, predictably, reduced adherence was more prevalent in subjects who subsequently dropped out.




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Trends in Emergency Department Visits and Inpatient Admissions for Hyperglycemic Crises in Adults With Diabetes in the U.S., 2006-2015

OBJECTIVE

To report U.S. national population-based rates and trends in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) among adults, in both the emergency department (ED) and inpatient settings.

RESEARCH DESIGN AND METHODS

We analyzed data from 1 January 2006 through 30 September 2015 from the Nationwide Emergency Department Sample and National Inpatient Sample to characterize ED visits and inpatient admissions with DKA and HHS. We used corresponding year cross-sectional survey data from the National Health Interview Survey to estimate the number of adults ≥18 years with diagnosed diabetes to calculate population-based rates for DKA and HHS in both ED and inpatient settings. Linear trends from 2009 to 2015 were assessed using Joinpoint software.

RESULTS

In 2014, there were a total of 184,255 and 27,532 events for DKA and HHS, respectively. The majority of DKA events occurred in young adults aged 18–44 years (61.7%) and in adults with type 1 diabetes (70.6%), while HHS events were more prominent in middle-aged adults 45–64 years (47.5%) and in adults with type 2 diabetes (88.1%). Approximately 40% of the hyperglycemic events were in lower-income populations. Overall, event rates for DKA significantly increased from 2009 to 2015 in both ED (annual percentage change [APC] 13.5%) and inpatient settings (APC 8.3%). A similar trend was seen for HHS (APC 16.5% in ED and 6.3% in inpatient). The increase was in all age-groups and in both men and women.

CONCLUSIONS

Causes of increased rates of hyperglycemic events are unknown. More detailed data are needed to investigate the etiology and determine prevention strategies.




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Differential Health Care Use, Diabetes-Related Complications, and Mortality Among Five Unique Classes of Patients With Type 2 Diabetes in Singapore: A Latent Class Analysis of 71,125 Patients

OBJECTIVE

With rising health care costs and finite health care resources, understanding the population needs of different type 2 diabetes mellitus (T2DM) patient subgroups is important. Sparse data exist for the application of population segmentation on health care needs among Asian T2DM patients. We aimed to segment T2DM patients into distinct classes and evaluate their differential health care use, diabetes-related complications, and mortality patterns.

RESEARCH DESIGN AND METHODS

Latent class analysis was conducted on a retrospective cohort of 71,125 T2DM patients. Latent class indicators included patient’s age, ethnicity, comorbidities, and duration of T2DM. Outcomes evaluated included health care use, diabetes-related complications, and 4-year all-cause mortality. The relationship between class membership and outcomes was evaluated with the appropriate regression models.

RESULTS

Five classes of T2DM patients were identified. The prevalence of depression was high among patients in class 3 (younger females with short-to-moderate T2DM duration and high psychiatric and neurological disease burden) and class 5 (older patients with moderate-to-long T2DM duration and high disease burden with end-organ complications). They were the highest tertiary health care users. Class 5 patients had the highest risk of myocardial infarction (hazard ratio [HR] 12.05, 95% CI 10.82–13.42]), end-stage renal disease requiring dialysis initiation (HR 25.81, 95% CI 21.75–30.63), stroke (HR 19.37, 95% CI 16.92–22.17), lower-extremity amputation (HR 12.94, 95% CI 10.90–15.36), and mortality (HR 3.47, 95% CI 3.17–3.80).

CONCLUSIONS

T2DM patients can be segmented into classes with differential health care use and outcomes. Depression screening should be considered for the two identified classes of patients.




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Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study

OBJECTIVE

The aim of this study was to quantify the excess risk of autoimmune hypothyroidism and hyperthyroidism, Addison disease, celiac disease, and atrophic gastritis in adults with type 1 diabetes (T1D) compared with nondiabetic individuals in Finland.

RESEARCH DESIGN AND METHODS

The study included 4,758 individuals with T1D from the Finnish Diabetic Nephropathy (FinnDiane) Study and 12,710 nondiabetic control individuals. The autoimmune diseases (ADs) were identified by linking the data with the Finnish nationwide health registries from 1970 to 2015.

RESULTS

The median age of the FinnDiane individuals at the end of follow-up in 2015 was 51.4 (interquartile range 42.6–60.1) years, and the median duration of diabetes was 35.5 (26.5–44.0) years. Of individuals with T1D, 22.8% had at least one additional AD, which included 31.6% of women and 14.9% of men. The odds ratios for hypothyroidism, hyperthyroidism, celiac disease, Addison disease, and atrophic gastritis were 3.43 (95% CI 3.09–3.81), 2.98 (2.27–3.90), 4.64 (3.71–5.81), 24.13 (5.60–104.03), and 5.08 (3.15–8.18), respectively, in the individuals with T1D compared with the control individuals. The corresponding ORs for women compared with men were 2.96 (2.53–3.47), 2.83 (1.87–4.28), 1.52 (1.15–2.02), 2.22 (0.83–5.91), and 1.36 (0.77–2.39), respectively, in individuals with T1D. Late onset of T1D and aging increased the risk of hypothyroidism, whereas young age at onset of T1D increased the risk of celiac disease.

CONCLUSIONS

This is one of the largest studies quantifying the risk of coexisting AD in adult individuals with T1D in the country with the highest incidence of T1D in the world. The results highlight the importance of continuous screening for other ADs in individuals with T1D.




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Risk of Ipsilateral Reamputation Following an Incident Toe Amputation Among U.S. Military Veterans With Diabetes, 2005-2016

OBJECTIVE

To assess whether the risk of subsequent lower-limb amputations and death following an initial toe amputation among individuals with diabetes has changed over time and varies by demographic characteristics and geographic region.

RESEARCH DESIGN AND METHODS

Using Veterans Health Administration (VHA) electronic medical records from 1 October 2004 to 30 September 2016, we determined risk of subsequent ipsilateral minor and major amputation within 1 year after an initial toe/ray amputation among veterans with diabetes. To assess changes in the annual rate of subsequent amputation over time, we estimated age-adjusted incidence of minor and major subsequent ipsilateral amputation for each year, separately for African Americans (AAs) and whites. Geographic variation was assessed across VHA markets (n = 89) using log-linear Poisson regression models adjusting for age and ethnoracial category.

RESULTS

Among 17,786 individuals who had an initial toe amputation, 34% had another amputation on the same limb within 1 year, including 10% who had a major ipsilateral amputation. Median time to subsequent ipsilateral amputation (minor or major) was 36 days. One-year risk of subsequent major amputation decreased over time, but risk of subsequent minor amputation did not. Risk of subsequent major ipsilateral amputation was higher in AAs than whites. After adjusting for age and ethnoracial category, 1-year risk of major subsequent amputation varied fivefold across VHA markets.

CONCLUSIONS

Nearly one-third of individuals require reamputation following an initial toe amputation, although risks of subsequent major ipsilateral amputation have decreased over time. Nevertheless, risks remain particularly high for AAs and vary substantially geographically.




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The Synergic Association of hs-CRP and Serum Amyloid P Component in Predicting All-Cause Mortality in Patients With Type 2 Diabetes

OBJECTIVE

Type 2 diabetes is characterized by increased death rate. In order to tackle this dramatic event, it becomes essential to discover novel biomarkers capable of identifying high-risk patients to be exposed to more aggressive preventive and treatment strategies. hs-CRP and serum amyloid P component (SAP) are two acute-phase inflammation proteins, which interact physically and share structural and functional features. We investigated their combined role in associating with and improving prediction of mortality in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Four cohorts comprising 2,499 patients with diabetes (643 all-cause deaths) were analyzed. The improvement of mortality prediction was addressed using two well-established prediction models, namely, EstimatioN oF mORtality risk in type 2 diabetiC patiEnts (ENFORCE) and Risk Equations for Complications of Type 2 Diabetes (RECODe).

RESULTS

Both hs-CRP and SAP were independently associated with all-cause mortality (hazard ratios [HRs] [95% CIs]: 1.46 [1.34–1.58] [P < 0.001] and 0.82 [0.76–0.89] [P < 0.001], respectively). Patients with SAP ≤33 mg/L were at increased risk of death versus those with SAP >33 mg/L only if hs-CRP was relatively high (>2 mg/L) (HR 1.96 [95% CI 1.52–2.54] [P < 0.001] and 1.20 [0.91–1.57] [P = 0.20] in hs-CRP >2 and ≤2 mg/L subgroups, respectively; hs-CRP-by-SAP strata interaction P < 0.001). The addition of hs-CRP and SAP significantly (all P < 0.05) improved several discrimination and reclassification measures of both ENFORCE and RECODe all-cause mortality prediction models.

CONCLUSIONS

In type 2 diabetes, hs-CRP and SAP show opposite and synergic associations with all-cause mortality. The use of both markers, possibly in combination with others yet to be unraveled, might improve the ability to predict the risk of death in the real-life setting.




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Multilevel Variation in Diabetes Screening Within an Integrated Health System

OBJECTIVE

Variation in diabetes screening in clinical practice is poorly described. We examined the interplay of patient, provider, and clinic factors explaining variation in diabetes screening within an integrated health care system in the U.S.

RESEARCH DESIGN AND METHODS

We conducted a retrospective cohort study of primary care patients aged 18–64 years with two or more outpatient visits between 2010 and 2015 and no diagnosis of diabetes according to electronic health record (EHR) data. Hierarchical three-level models were used to evaluate multilevel variation in screening at the patient, provider, and clinic levels across 12 clinics. Diabetes screening was defined by a resulted gold standard screening test.

RESULTS

Of 56,818 patients, 70% completed diabetes screening with a nearly twofold variation across clinics (51–92%; P < 0.001). Of those meeting American Diabetes Association (ADA) (69%) and U.S. Preventive Services Task Force (USPSTF) (36%) screening criteria, three-quarters were screened with a nearly twofold variation across clinics (ADA 53–92%; USPSTF 49–93%). The yield of ADA and USPSTF screening was similar for diabetes (11% vs. 9%) and prediabetes (38% vs. 36%). Nearly 70% of patients not eligible for guideline-based screening were also tested. The USPSTF guideline missed more cases of diabetes (6% vs. 3%) and prediabetes (26% vs. 19%) than the ADA guideline. After adjustment for patient, provider, and clinic factors and accounting for clustering, twofold variation in screening by provider and clinic remained (median odds ratio 1.97; intraclass correlation 0.13).

CONCLUSIONS

Screening practices vary widely and are only partially explained by patient, provider, and clinic factors available in the EHR. Clinical decision support and system-level interventions are needed to optimize screening practices.




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Trends in Bone Mineral Density, Osteoporosis, and Osteopenia Among U.S. Adults With Prediabetes, 2005-2014

OBJECTIVE

We aimed to evaluate trends in bone mineral density (BMD) and the prevalence of osteoporosis/osteopenia in U.S. adults with prediabetes and normal glucose regulation (NGR) and further investigate the association among prediabetes, osteopenia/osteoporosis, and fracture.

RESEARCH DESIGN AND METHODS

We collected and analyzed data from the U.S. National Health and Nutrition Examination Surveys during the period from 2005 to 2014. Femoral neck and lumbar spine BMD data were available for 5,310 adults with prediabetes and 5,162 adults with NGR >40 years old.

RESULTS

A shift was observed toward a lower BMD and a higher prevalence of osteopenia/osteoporosis at the femoral neck and lumbar spine in U.S. adults >40 years old with prediabetes since 2005, especially in men <60 and women ≥60 years old. A shift toward a higher prevalence of osteopenia/osteoporosis at the femoral neck was also observed in adults >40 years old with NGR. Moreover, prediabetes was associated with a higher prevalence of hip fracture, although participants with prediabetes had higher BMD and a lower prevalence of osteopenia/osteoporosis at the femoral neck.

CONCLUSIONS

There was a declining trend in BMD from 2005 to 2014 in U.S. adults >40 years old with prediabetes and NGR, and this trend was more significant in men <60 years old. Populations with prediabetes may be exposed to relatively higher BMD but a higher prevalence of fracture.




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Possible Modifiers of the Association Between Change in Weight Status From Child Through Adult Ages and Later Risk of Type 2 Diabetes

OBJECTIVE

We investigated the association between changes in weight status from childhood through adulthood and subsequent type 2 diabetes risks and whether educational attainment, smoking, and leisure time physical activity (LTPA) modify this association.

RESEARCH DESIGN AND METHODS

Using data from 10 Danish and Finnish cohorts including 25,283 individuals, childhood BMI at 7 and 12 years was categorized as normal or high using age- and sex-specific cutoffs (<85th or ≥85th percentile). Adult BMI (20–71 years) was categorized as nonobese or obese (<30.0 or ≥30.0 kg/m2, respectively). Associations between BMI patterns and type 2 diabetes (989 women and 1,370 men) were analyzed using Cox proportional hazards regressions and meta-analysis techniques.

RESULTS

Compared with individuals with a normal BMI at 7 years and without adult obesity, those with a high BMI at 7 years and adult obesity had higher type 2 diabetes risks (hazard ratio [HR]girls 5.04 [95% CI 3.92–6.48]; HRboys 3.78 [95% CI 2.68–5.33]). Individuals with a high BMI at 7 years but without adult obesity did not have a higher risk (HRgirls 0.74 [95% CI 0.52–1.06]; HRboys 0.93 [95% CI 0.65–1.33]). Education, smoking, and LTPA were associated with diabetes risks but did not modify or confound the associations with BMI changes. Results for 12 years of age were similar.

CONCLUSIONS

A high BMI in childhood was associated with higher type 2 diabetes risks only if individuals also had obesity in adulthood. These associations were not influenced by educational and lifestyle factors, indicating that BMI is similarly related to the risk across all levels of these factors.




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Early Childhood Antibiotic Treatment for Otitis Media and Other Respiratory Tract Infections Is Associated With Risk of Type 1 Diabetes: A Nationwide Register-Based Study With Sibling Analysis

OBJECTIVE

The effect of early-life antibiotic treatment on the risk of type 1 diabetes is debated. This study assessed this question, applying a register-based design in children up to age 10 years including a large sibling-control analysis.

RESEARCH DESIGN AND METHODS

All singleton children (n = 797,318) born in Sweden between 1 July 2005 and 30 September 2013 were included and monitored to 31 December 2014. Cox proportional hazards models, adjusted for parental and perinatal characteristics, were applied, and stratified models were used to account for unmeasured confounders shared by siblings.

RESULTS

Type 1 diabetes developed in 1,297 children during the follow-up (median 4.0 years [range 0–8.3]). Prescribed antibiotics in the 1st year of life (23.8%) were associated with an increased risk of type 1 diabetes (adjusted hazard ratio [HR] 1.19 [95% CI 1.05–1.36]), with larger effect estimates among children delivered by cesarean section (P for interaction = 0.016). The association was driven by exposure to antibiotics primarily used for acute otitis media and respiratory tract infections. Further, we found an association of antibiotic prescriptions in pregnancy (22.5%) with type 1 diabetes (adjusted HR 1.15 [95% CI 1.00–1.32]). In general, sibling analysis supported these results, albeit often with statistically nonsignificant associations.

CONCLUSIONS

Dispensed prescription of antibiotics, mainly for acute otitis media and respiratory tract infections, in the 1st year of life is associated with an increased risk of type 1 diabetes before age 10 years, most prominently in children delivered by cesarean section.




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Incidence and Associations of Chronic Kidney Disease in Community Participants With Diabetes: A 5-Year Prospective Analysis of the EXTEND45 Study

OBJECTIVE

To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in people with diabetes.

RESEARCH DESIGN AND METHODS

We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006–2014) that linked the Sax Institute’s 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement <60 mL/min/1.73 m2 recorded during the follow-up period. Participants with eGFR < 60 mL/min/1.73 m2 at baseline were excluded. We used Poisson regression to estimate the incidence of eGFR <60 mL/min/1.73 m2 and multivariable Cox regression to examine factors associated with the study outcome.

RESULTS

Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR <60 mL/min/1.73 m2 over a median follow-up time of 5.7 years (interquartile range, 3.0–5.9 years). The eGFR <60 mL/min/1.73 m2 incidence rate per 100 person-years was 6.0 (95% CI 5.7–6.3) overall, 1.5 (1.3–1.9) in participants aged 45–54 years, 3.7 (3.4–4.0) for 55–64 year olds, 7.6 (7.1–8.1) for 65–74 year olds, 15.0 (13.0–16.0) for 75–84 year olds, and 26.0 (22.0–32.0) for those aged 85 years and over. In a fully adjusted multivariable model incidence was independently associated with age (hazard ratio 1.23 per 5-year increase; 95% CI 1.19–1.26), geography (outer regional and remote versus major city: 1.36; 1.17–1.58), obesity (obese class III versus normal: 1.44; 1.16–1.80), and the presence of hypertension (1.52; 1.33–1.73), coronary heart disease (1.13; 1.02–1.24), cancer (1.30; 1.14–1.50), and depression/anxiety (1.14; 1.01–1.27).

CONCLUSIONS

In participants with diabetes, the incidence of an eGFR <60 mL/min/1.73 m2 was high. Older age, remoteness of residence, and the presence of various comorbid conditions were associated with higher incidence.




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Initial Glycemic Control and Care Among Younger Adults Diagnosed With Type 2 Diabetes

OBJECTIVE

The prevalence of type 2 diabetes is increasing among adults under age 45. Onset of type 2 diabetes at a younger age increases an individual’s risk for diabetes-related complications. Given the lasting benefits conferred by early glycemic control, we compared glycemic control and initial care between adults with younger onset (21–44 years) and mid-age onset (45–64 years) of type 2 diabetes.

RESEARCH DESIGN AND METHODS

Using data from a large, integrated health care system, we identified 32,137 adults (aged 21–64 years) with incident diabetes (first HbA1c ≥6.5% [≥48 mmol/mol]). We excluded anyone with evidence of prior type 2 diabetes, gestational diabetes mellitus, or type 1 diabetes. We used generalized linear mixed models, adjusting for demographic and clinical variables, to examine differences in glycemic control and care at 1 year.

RESULTS

Of identified individuals, 26.4% had younger-onset and 73.6% had mid-age–onset type 2 diabetes. Adults with younger onset had higher initial mean HbA1c values (8.9% [74 mmol/mol]) than adults with onset in mid-age (8.4% [68 mmol/mol]) (P < 0.0001) and lower odds of achieving an HbA1c <7% (<53 mmol/mol) 1 year after the diagnosis (adjusted odds ratio [aOR] 0.70 [95% CI 0.66–0.74]), even after accounting for HbA1c at diagnosis. Adults with younger onset had lower odds of in-person primary care contact (aOR 0.82 [95% CI 0.76–0.89]) than those with onset during mid-age, but they did not differ in telephone contact (1.05 [0.99–1.10]). Adults with younger onset had higher odds of starting metformin (aOR 1.20 [95% CI 1.12–1.29]) but lower odds of adhering to that medication (0.74 [0.69–0.80]).

CONCLUSIONS

Adults with onset of type 2 diabetes at a younger age were less likely to achieve glycemic control at 1 year following diagnosis, suggesting the need for tailored care approaches to improve outcomes for this high-risk patient population.




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Global Disability Burdens of Diabetes-Related Lower-Extremity Complications in 1990 and 2016

OBJECTIVE

No study has reported global disability burden estimates for individual diabetes-related lower-extremity complications (DRLECs). The Global Burden of Disease (GBD) study presents a robust opportunity to address this gap.

RESEARCH DESIGN AND METHODS

GBD 2016 data, including prevalence and years lived with disability (YLDs), for the DRLECs of diabetic neuropathy, foot ulcer, and amputation with and without prosthesis were used. The GBD estimated prevalence using data from systematic reviews and DisMod-MR 2.1, a Bayesian meta-regression tool. YLDs were estimated as the product of prevalence estimates and disability weights for each DRLEC. We reported global and sex-, age-, region-, and country-specific estimates for each DRLEC for 1990 and 2016.

RESULTS

In 2016, an estimated 131 million people (1.8% of the global population) had DRLECs. An estimated 16.8 million YLDs (2.1% global YLDs) were caused by DRLECs, including 12.9 million (95% uncertainty interval 8.30–18.8) from neuropathy only, 2.5 million (1.7–3.6) from foot ulcers, 1.1 million (0.7–1.4) from amputation without prosthesis, and 0.4 million (0.3–0.5) from amputation with prosthesis. Age-standardized YLD rates of all DRLECs increased by between 14.6% and 31.0% from 1990 estimates. Male-to-female YLD ratios ranged from 0.96 for neuropathy only to 1.93 for foot ulcers. The 50- to 69-year-old age-group accounted for 47.8% of all YLDs from DRLECs.

CONCLUSIONS

These first-ever global estimates suggest that DRLECs are a large and growing contributor to the disability burden worldwide and disproportionately affect males and middle- to older-aged populations. These findings should facilitate policy makers worldwide to target strategies at populations disproportionately affected by DRLECs.




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Associations Between Racial and Ethnic Groups and Foot Self-Inspection in People With Diabetes

OBJECTIVE

Daily foot self-inspection may permit earlier detection and treatment of a foot lesion, reducing the risk of infection and lower-limb amputation (LLA). Though race and ethnicity are strongly associated with LLA risk, with higher risk seen in African Americans (AA), American Indians/Alaska Natives (AI/AN), and Native Hawaiians/Pacific Islanders (NH/PI), associations between foot self-inspection and racial and ethnic groups are inconsistent. We aimed to assess differences in foot self-inspection among people with diabetes by race/ethnicity.

RESEARCH DESIGN AND METHODS

Using national, cross-sectional data from the 2015–2017 Behavioral Risk Factor Surveillance System surveys and including 88,424 individuals with diabetes, we estimated prevalence ratios (PRs) and associated 95% CIs of daily foot checking for sores or irritation by racial and ethnic groups using log-binomial linear regression models, after accounting for survey weights.

RESULTS

Compared with whites (who had a weighted prevalence [P] of daily foot self-inspection of 57%), AA (P 67%, PR 1.18 [95% CI 1.14, 1.23]), AI/AN (P 66%, PR 1.15 [95% CI 1.07, 1.25]), and NH/PI (P 71%, PR 1.25 [95% CI 1.03, 1.52]) had higher prevalences of daily foot self-inspection. The prevalence of daily foot inspection was significantly lower among Asians (P 35%, PR 0.62 [95% CI 0.48, 0.81]) and Hispanics (P 53%, PR 0.93 [95% CI 0.88, 0.99]) compared with whites. Associations did not vary importantly by insulin use, years since diabetes diagnosis, or having received diabetes self-management education.

CONCLUSIONS

The higher frequency of foot self-inspection in racial and ethnic groups at elevated risk of diabetes-related LLA is not sufficient to eliminate LLA disparities; additional interventions are needed to achieve this aim.




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The Long-term Effects of Metformin on Patients With Type 2 Diabetic Kidney Disease

OBJECTIVE

Metformin is the first pharmacological option for treating type 2 diabetes. However, the use of this drug is not recommended in individuals with impaired kidney function because of the perceived risk of lactic acidosis. We aimed to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD).

RESEARCH DESIGN AND METHODS

We conducted a retrospective observational cohort study of 10,426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. Taking into account the possibility that patients with less severe disease were prescribed metformin, propensity score matching (PSM) was conducted.

RESULTS

All-cause mortality and incident ESRD were lower in the metformin group according to the multivariate Cox analysis. Because the two groups had significantly different baseline characteristics, PSM was performed. After matching, metformin usage was still associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% CI 0.57–0.73; P < 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58–0.77; P < 0.001). Only one event of metformin-associated lactic acidosis was recorded. In both the original and PSM groups, metformin usage did not increase the risk of lactic acidosis events from all causes (aHR 0.92; 95% CI 0.668–1.276; P = 0.629).

CONCLUSIONS

In the present retrospective study, metformin usage in advanced chronic kidney disease (CKD) patients, especially those with CKD 3B, decreased the risk of all-cause mortality and incident ESRD. Additionally, metformin did not increase the risk of lactic acidosis. However, considering the remaining biases even after PSM, further randomized controlled trials are needed to change real-world practice.




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A Special Thanks to the Reviewers of Diabetes Care




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In This Issue of Diabetes Care




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Markers of Early Life Infection in Relation to Adult Diabetes: Prospective Evidence From a National Birth Cohort Study Over Four Decades




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Facility-Level Variation in Cardiac Stress Test Use Among Patients With Diabetes: Findings From the Veterans Affairs National Database




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Bariatric Surgery in Patients With Obesity and Latent Autoimmune Diabetes in Adults (LADA)




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Diabetes Care




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Cardiac biomarkers are prognostic in systemic light chain amyloidosis with no cardiac involvement by standard criteria

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 μmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (P=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.




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Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation

Mutation and translocation of fibroblast growth factor receptors often lead to aberrant signaling and cancer. This work focuses on the t(8;22)(p11;q11) chromosomal translocation which creates the breakpoint cluster region (BCR) fibroblast growth factor receptor1 (FGFR1) (BCR-FGFR1) fusion protein. This fusion occurs in stem cell leukemia/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-cell lymphoma. This work focuses on the biochemical characterization of BCR-FGFR1 and identification of novel therapeutic targets. The tyrosine kinase activity of FGFR1 is required for biological activity as shown using transformation assays, interleukin-3 independent cell proliferation, and liquid chromatography/mass spectroscopy analyses. Furthermore, BCR contributes a coiled-coil oligomerization domain, also essential for oncogenic transformation by BCR-FGFR1. The importance of salt bridge formation within the coiled-coil domain is demonstrated, as disruption of three salt bridges abrogates cellular transforming ability. Lastly, BCR-FGFR1 acts as a client of the chaperonin heat shock protein 90 (Hsp90), suggesting that BCR-FGFR1 relies on Hsp90 complex to evade proteasomal degradation. Transformed cells expressing BCR-FGFR1 are sensitive to the Hsp90 inhibitor Ganetespib, and also respond to combined treatment with Ganetespib plus the FGFR inhibitor BGJ398. Collectively, these data suggest novel therapeutic approaches for future stem cell leukemia/lymphoma treatment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex.




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Long-term outcome of a randomized controlled study in patients with newly diagnosed severe aplastic anemia treated with antithymocyte globulin and cyclosporine, with or without granulocyte colony-stimulating factor: a Severe Aplastic Anemia Working Party

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF (P=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (P=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (P=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (P=0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942).




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Prion protein deficiency impairs hematopoietic stem cell determination and sensitizes myeloid progenitors to irradiation

Highly conserved among species and expressed in various types of cells, numerous roles have been attributed to the cellular prion protein (PrPC). In hematopoiesis, PrPC regulates hematopoietic stem cell self-renewal but the mechanisms involved in this regulation are unknown. Here we show that PrPC regulates hematopoietic stem cell number during aging and their determination towards myeloid progenitors. Furthermore, PrPC protects myeloid progenitors against the cytotoxic effects of total body irradiation. This radioprotective effect was associated with increased cellular prion mRNA level and with stimulation of the DNA repair activity of the Apurinic/pyrimidinic endonuclease 1, a key enzyme of the base excision repair pathway. Altogether, these results show a previously unappreciated role of PrPC in adult hematopoiesis, and indicate that PrPC-mediated stimulation of BER activity might protect hematopoietic progenitors from the cytotoxic effects of total body irradiation.




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Severe treatment-refractory T-cell-mediated immune skin toxicities observed with obinutuzumab/rituximab-atezo-pola in two patients with follicular lymphoma




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Early high plasma ST2, the decoy IL-33 receptor, in children undergoing hematopoietic cell transplantation is associated with the development of post-transplant diabetes mellitus




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CRISPR/Cas9-mediated gene deletion efficiently retards the progression of Philadelphia-positive acute lymphoblastic leukemia in a p210 BCR-ABL1T315I mutation mouse model




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EZH2 mutations and impact on clinical outcome: an analysis in 1,604 patients with newly diagnosed acute myeloid leukemia




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Erratum. WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic {beta}-Cells. Diabetes 2019;68:377-386




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Systematic Genetic Study of Youth With Diabetes in a Single Country Reveals the Prevalence of Diabetes Subtypes, Novel Candidate Genes, and Response to Precision Therapy

Identifying gene variants causing monogenic diabetes (MD) increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of MD in youth with diabetes in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young-adult patients with diabetes in Lithuania (n = 1,209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients (n = 153) using targeted high-throughput sequencing of >300 potential candidate genes. In this group, 40.7% had MD, with the highest percentage (100%) in infants (diagnosis at ages 0–12 months), followed by those diagnosed at ages >1–18 years (40.3%) and >18–25 years (22.2%). The overall prevalence of MD in youth with diabetes in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with MD. Prospective treatment change was successful in >50% of eligible candidates, with C-peptide >252 pmol/L emerging as the best prognostic factor.




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MG53 Does Not Manifest the Development of Diabetes in db/db Mice

MG53 is a member of the TRIM protein family that is predominantly expressed in striated muscles and participates in cell membrane repair. Controversy exists regarding MG53’s role in insulin signaling and manifestation of diabetes. We generated db/db mice with either whole-body ablation or sustained elevation of MG53 in the bloodstream in order to evaluate the physiological function of MG53 in diabetes. To quantify the amount of MG53 protein in circulation, we developed a monoclonal antibody against MG53 with high specificity. Western blot using this antibody revealed lower or no change of serum MG53 levels in db/db mice or patients with diabetes compared with control subjects. Neither whole-body ablation of MG53 nor sustained elevation of MG53 in circulation altered insulin signaling and glucose handling in db/db mice. Instead, mice with ablation of MG53 were more susceptible to streptozotocin-induced dysfunctional handling of glucose compared with the wild-type littermates. Alkaline-induced corneal injury demonstrated delayed healing in db/db mice, which was restored by topical administration of recombinant human (rh)MG53. Daily intravenous administration of rhMG53 in rats at concentrations up to 10 mg/kg did not produce adverse effects on glucose handling. These findings challenge the hypothetical function of MG53 as a causative factor for the development of diabetes. Our data suggest that rhMG53 is a potentially safe and effective biologic to treat diabetic oculopathy in rodents.




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Effects of Vitamin D Receptor Knockout and Vitamin D Deficiency on Corneal Epithelial Wound Healing and Nerve Density in Diabetic Mice

Diabetic keratopathy occurs in ~70% of all people with diabetes. This study was designed to examine the effects of vitamin D receptor knockout (VDR–/–) and vitamin D deficiency (VDD) on corneal epithelial wound healing and nerve density in diabetic mice. Diabetes was induced using the low-dose streptozotocin method. Corneal epithelial wounds were created using an Algerbrush, and wound healing was monitored over time. Corneal nerve density was measured in unwounded mice. VDR–/– and VDD diabetic mice (diabetic for 8 and 20 weeks, respectively) had slower healing ratios than wild-type diabetic mice. VDR–/– and VDD diabetic mice also showed significantly decreased nerve density. Reduced wound healing ratios and nerve densities were not fully rescued by a supplemental diet rich in calcium, lactose, and phosphate. We conclude that VDR–/– and VDD significantly reduce both corneal epithelial wound healing and nerve density in diabetic mice. Because the supplemental diet did not rescue wound healing or nerve density, these effects are likely not specifically related to hypocalcemia. This work supports the hypothesis that low vitamin D levels can exacerbate preexisting ophthalmic conditions, such as diabetes.




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Impairment in Baroreflex Sensitivity in Recent-Onset Type 2 Diabetes Without Progression Over 5 Years

Impaired baroreflex sensitivity (BRS) predicts cardiovascular mortality and is prevalent in long-term diabetes. We determined spontaneous BRS in patients with recent-onset diabetes and its temporal sequence over 5 years by recording beat-to-beat blood pressure and R-R intervals over 10 min. Four time domain and four frequency domain BRS indices were computed in participants from the German Diabetes Study baseline cohort with recent-onset type 1/type 2 diabetes (n = 206/381) and age-matched glucose-tolerant control subjects (control 1/control 2: n = 65/83) and subsets of consecutive participants with type 1/type 2 diabetes who reached the 5-year follow-up (n = 84/137). Insulin sensitivity (M-value) was determined using a hyperinsulinemic-euglycemic clamp. After appropriate adjustment, three frequency domain BRS indices were reduced in type 2 diabetes compared with control 2 and were positively associated with the M-value and inversely associated with fasting glucose and HbA1c (P < 0.05), whereas BRS was preserved in type 1 diabetes. After 5 years, a decrease in one and four BRS indices was observed in patients with type 1 and type 2 diabetes, respectively (P < 0.05), which was explained by the physiologic age-dependent decline. Unlike patients with well-controlled recent-onset type 1 diabetes, those with type 2 diabetes show early baroreflex dysfunction, likely due to insulin resistance and hyperglycemia, albeit without progression over 5 years.




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Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m2, higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.




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Claudin-5 Redistribution Induced by Inflammation Leads to Anti-VEGF-Resistant Diabetic Macular Edema

Approximately 40% of patients with diabetic macular edema (DME) are resistant to anti–vascular endothelial growth factor (VEGF) therapy (rDME). Here, we demonstrate that significant correlations between inflammatory cytokines and VEGF, as observed in naive DME, are lost in patients with rDME. VEGF overexpression in the mouse retina caused delayed inflammatory cytokine upregulation, monocyte/macrophage infiltration (CD11b+ Ly6C+ CCR2+ cells), macrophage/microglia activation (CD11b+ CD80+ cells), and blood-retinal barrier disruption due to claudin-5 redistribution, which did not recover with VEGF blockade alone. Phosphorylated protein analysis of VEGF-overexpressed retinas revealed rho-associated coiled-coil–containing protein kinase (ROCK) activation. Administration of ripasudil, a selective ROCK inhibitor, attenuated retinal inflammation and claudin-5 redistribution. Ripasudil also contributed to the stability of claudin-5 expression by both transcriptional enhancement and degradation suppression in inflammatory cytokine–stimulated endothelium. Notably, the anti-VEGF agent and the ROCK inhibitor were synergic in suppressing cytokine upregulation, monocyte/macrophage infiltration, macrophage/microglia activation, and claudin-5 redistribution. Furthermore, in vitro analysis confirmed that claudin-5 redistribution depends on ROCK2 but not on ROCK1. This synergistic effect was also confirmed in human rDME cases. Our results suggest that ROCK-mediated claudin-5 redistribution by inflammation is a key mechanism in the anti-VEGF resistance of DME.




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Microencapsulated G3C Hybridoma Cell Graft Delays the Onset of Spontaneous Diabetes in NOD Mice by an Expansion of Gitr+ Treg Cells

As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3+ Treg-cell expansion in the spleen of wild-type mice but not in Gitr–/– mice. G3C/cps also induced the expansion of nonconventional Cd4+Cd25–/lowFoxp3lowGitrint/high (GITR single-positive [sp]) Tregs. Both Cd4+Cd25+GitrhighFoxp3+ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.




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Role of Proinsulin Self-Association in Mutant INS Gene-Induced Diabetes of Youth

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant INS gene–induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.




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HRD1, an Important Player in Pancreatic {beta}-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice

Inadequate insulin secretion in response to glucose is an important factor for β-cell failure in type 2 diabetes (T2D). Although HMG-CoA reductase degradation 1 (HRD1), a subunit of the endoplasmic reticulum–associated degradation complex, plays a pivotal role in β-cell function, HRD1 elevation in a diabetic setting contributes to β-cell dysfunction. We report in this study the excessive HRD1 expression in islets from humans with T2D and T2D mice. Functional studies reveal that β-cell–specific HRD1 overexpression triggers impaired insulin secretion that will ultimately lead to severe hyperglycemia; by contrast, HRD1 knockdown improves glucose control and response in diabetic models. Proteomic analysis results reveal a large HRD1 interactome, which includes v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), a master regulator of genes implicated in the maintenance of β-cell function. Furthermore, mechanistic assay results indicate that HRD1 is a novel E3 ubiquitin ligase that targets MafA for ubiquitination and degradation in diabetic β-cells, resulting in cytoplasmic accumulation of MafA and in the reduction of its biological function in the nucleus. Our results not only reveal the pathological importance of excessive HRD1 in β-cell dysfunction but also establish the therapeutic importance of targeting HRD1 in order to prevent MafA loss and suppress the development of T2D.




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Vitamin D Receptor Overexpression in {beta}-Cells Ameliorates Diabetes in Mice

Vitamin D deficiency has been associated with increased incidence of diabetes, both in humans and in animal models. In addition, an association between vitamin D receptor (VDR) gene polymorphisms and diabetes has also been described. However, the involvement of VDR in the development of diabetes, specifically in pancreatic β-cells, has not been elucidated yet. Here, we aimed to study the role of VDR in β-cells in the pathophysiology of diabetes. Our results indicate that Vdr expression was modulated by glucose in healthy islets and decreased in islets from both type 1 diabetes and type 2 diabetes mouse models. In addition, transgenic mice overexpressing VDR in β-cells were protected against streptozotocin-induced diabetes and presented a preserved β-cell mass and a reduction in islet inflammation. Altogether, these results suggest that sustained VDR levels in β-cells may preserve β-cell mass and β-cell function and protect against diabetes.




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DLL1- and DLL4-Mediated Notch Signaling Is Essential for Adult Pancreatic Islet Homeostasis

Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and DLL4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult β-cells display improved glucose tolerance, increased glucose-stimulated insulin secretion, and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that Notch ligands play specific roles in the adult pancreas and highlight a novel function of the Delta/Notch pathway in β-cell insulin secretion.




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Apolipoprotein M and Sphingosine-1-Phosphate: A Potentially Antidiabetic Tandem Carried by HDL