bet {beta}-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1 By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D. Full Article
bet Maternal Type 1 Diabetes Reduces Autoantigen-Responsive CD4+ T Cells in Offspring By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 Autoimmunity against pancreatic β-cell autoantigens is a characteristic of childhood type 1 diabetes (T1D). Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with T1D are protected from this process. The aim of this study was to determine whether the protection conferred by maternal T1D is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with T1D had reduced cord blood CD4+ T-cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4+ T cells, and improved regulation of CD4+ T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with T1D. Maternal T1D was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal T1D environment improves neonatal immune tolerance against the autoantigen (pro)insulin. Full Article
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bet Moving Beyond “Root Causes:” The Complicated Relationship between Development and Migration By www.migrationpolicy.org Published On :: Tue, 09 Jan 2018 18:12:25 -0500 Development assistance may be a blunt tool for reshaping migration patterns—and indeed one that could increase flows over the short term. Shifting the focus away from increasing individuals’ skills and assets toward investments in the broader economic or governance structures that are a prerequisite for growth and stability may offer more alternatives to emigration in the long run. Full Article
bet Suicide Risk Assessment in Youth and Young Adults With Type 1 Diabetes By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 OBJECTIVE To describe sociodemographic and clinical characteristics of youth and young adults with type 1 diabetes who endorsed suicidal ideations as part of routine depression screening and the results of their suicide risk assessments. RESEARCH DESIGN AND METHODS The Patient Health Questionnaire–9 was used to assess depressive symptoms and suicide/death ideation in 550 youth and young adults with type 1 diabetes ages 10–24 years. Only individuals who endorsed suicidal/death ideations (n = 49) completed a standardized suicide risk assessment protocol and safety planning. RESULTS Nine percent of individuals endorsed suicidal/death ideation and of those, 83.4% reported clinically elevated depressive symptoms; 16% made a previous suicide attempt. No youth (n = 39) or young adults (n = 11) disclosed current plans or preparations for suicide, but five who expressed suicidal ideation acknowledged the lethality of insulin for an attempt. Three previously used insulin to attempt suicide. The overwhelming majority of individuals were classified as being low risk for future suicide attempt/completion. None were hospitalized as a part of the suicide risk assessment, and no suicide completions have occurred. CONCLUSIONS The findings of this study provide initial insight into the behaviors and cognitions of youth and young adults with type 1 diabetes who experience suicidal and death ideations. Comprehensive suicide risk assessment and safety planning are feasible during routine type 1 diabetes clinic appointments. Full Article
bet Randomized Study to Evaluate the Impact of Telemedicine Care in Patients With Type 1 Diabetes With Multiple Doses of Insulin and Suboptimal HbA1c in Andalusia (Spain): PLATEDIAN Study By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 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) 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. Full Article
bet Diabetes INSIDE: Improving Population HbA1c Testing and Targets in Primary Care With a Quality Initiative By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 OBJECTIVE To improve outcomes of patients with adult type 2 diabetes by decreasing HbA1c undertesting, reducing the proportion of patients with poor glycemic control, and lowering mean HbA1c levels using a quality improvement (QI) program. RESEARCH DESIGN AND METHODS Six years of outpatient electronic health record (EHR) data were analyzed for care gaps before and 2 years after implementing a QI initiative in an urban academic medical center. QI strategies included 1) individual provider and departmental outcome reports, 2) patient outreach programs to address timely follow-up care, 3) a patient awareness campaign to improve understanding of achieving clinical goals, 4) improving EHR data capture to improve population monitoring, and 5) professional education. RESULTS Analysis (January 2010 to May 2018) of 7,798 patients from Tulane Medical Center (mean age 61 years, 57% female, 62% black, 97% insured) with 136,004 visits showed target improvements. A Cox proportional hazards model controlling for age, sex, race, and HbA1c level showed a statistically significant reduction in HbA1c undertesting >6 months (hazard ratio 1.20 ± 0.07). Statistical process control charts showed 15.5% relative improvement in the patient proportion with HbA1c >9% (75 mmol/mol) from 13% to 11% (P < 10–6) following QI interventions and a 2.1% improvement of population mean HbA1c from 7.4% (57 mmol/mol) to 7.2% (55 mmol/mol) (P < 10–6). CONCLUSIONS Multidisciplinary QI teams using EHR data to design interventions for providers and patients produced statistically significant improvements in both care process and clinical outcome goals. Full Article
bet Sex Difference in Effects of Low-Dose Aspirin on Prevention of Dementia in Patients With Type 2 Diabetes: A Long-term Follow-up Study of a Randomized Clinical Trial By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 OBJECTIVE To evaluate and compare the efficacy of long-term use of low-dose aspirin for the prevention of dementia in men and women. RESEARCH DESIGN AND METHODS This study is a follow-up cohort study of the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial, which was a randomized, open-label, standard care–controlled trial examining the effects of low-dose aspirin on cardiovascular events. We followed up 2,536 Japanese patients with type 2 diabetes (T2D) enrolled in the JPAD trial from 2002 to 2017. The primary outcome of this post hoc analysis was the incidence of dementia, which was defined by the prescription of antidementia drugs or admission due to dementia. RESULTS Among the originally enrolled patients, 2,121 (84%) retained their original allocation. During a median follow-up of 11.4 years, 128 patients developed dementia. The overall effect of low-dose aspirin on the prevention of dementia adjusted for age, sex, and other established risk factors was not significant (hazard ratio [HR] 0.82, 95% CI 0.58–1.16). However, a significant reduction was seen in the risk of dementia in women (HR 0.58, 95% CI 0.36–0.95), but not in men (HR 1.27, 95% CI 0.75–2.13) (Pinteraction = 0.03). CONCLUSIONS Long-term use of low-dose aspirin may reduce the risk for dementia in women with T2D. Full Article
bet Late Relapse of Diabetes After Bariatric Surgery: Not Rare, but Not a Failure By care.diabetesjournals.org Published On :: 2020-02-20T11:55:29-08:00 OBJECTIVE To characterize the status of cardiometabolic risk factors after late relapse of type 2 diabetes mellitus (T2DM) and to identify factors predicting relapse after initial diabetes remission following bariatric surgery to construct prediction models for clinical practice. RESEARCH DESIGN AND METHODS Outcomes of 736 patients with T2DM who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at an academic center (2004–2012) and had ≥5 years’ glycemic follow-up were assessed. Of 736 patients, 425 (58%) experienced diabetes remission (HbA1c <6.5% [48 mmol/mol] with patients off medications) in the 1st year after surgery. These 425 patients were followed for a median of 8 years (range 5–14) to characterize late relapse of diabetes. RESULTS In 136 (32%) patients who experienced late relapse, a statistically significant improvement in glycemic control, number of diabetes medications including insulin use, blood pressure, and lipid profile was still observed at long-term. Independent baseline predictors of late relapse were preoperative number of diabetes medications, duration of T2DM before surgery, and SG versus RYGB. Furthermore, patients who relapsed lost less weight during the 1st year after surgery and regained more weight afterward. Prediction models were constructed and externally validated. CONCLUSIONS While late relapse of T2DM is a real phenomenon (one-third of our cohort), it should not be considered a failure, as the trajectory of the disease and its related cardiometabolic risk factors is changed favorably after bariatric surgery. Earlier surgical intervention, RYGB (compared with SG) and more weight loss (less late weight regain) are associated with less diabetes relapse in the long-term. Full Article
bet Intellectual Disability in KATP Channel Neonatal Diabetes By care.diabetesjournals.org Published On :: 2020-02-20T11:55:29-08:00 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 about patients carrying the heaviest burden. RESEARCH DESIGN AND METHODS We assessed the intellectual functioning and mental health of the complete Norwegian population with 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 child. 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. Full Article
bet Glucosamine Use, Inflammation, and Genetic Susceptibility, and Incidence of Type 2 Diabetes: A Prospective Study in UK Biobank By care.diabetesjournals.org Published On :: 2020-03-20T11:50:34-07:00 OBJECTIVE Glucosamine is a widely used supplement typically taken for osteoarthritis and joint pain. Emerging evidence suggests potential links of glucosamine with glucose metabolism, inflammation, and cardiometabolic risk. We prospectively analyzed the association of habitual glucosamine use with risk of type 2 diabetes (T2D) and assessed whether genetic susceptibility and inflammation status might modify the association. RESEARCH DESIGN AND METHODS This study analyzed 404,508 participants from the UK Biobank who were free of diabetes, cancer, or cardiovascular disease at baseline and completed the questionnaire on supplement use. Cox proportional hazards models were used to evaluate the association between habitual use of glucosamine and risk of incident T2D. RESULTS During a median of 8.1 years of follow-up, 7,228 incident cases of T2D were documented. Glucosamine use was associated with a significantly lower risk of T2D (hazard ratio 0.83, 95% CI 0.78–0.89) after adjustment for age, sex, BMI, race, center, Townsend deprivation index, lifestyle factors, history of disease, and other supplement use. This inverse association was more pronounced in participants with a higher blood level of baseline C-reactive protein than in those with a lower level of this inflammation marker (P-interaction = 0.02). A genetic risk score for T2D did not modify this association (P-interaction = 0.99). CONCLUSIONS Our findings indicate that glucosamine use is associated with a lower risk of incident T2D. Full Article
bet Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes By care.diabetesjournals.org Published On :: 2020-03-20T11:50:34-07:00 OBJECTIVE Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients. RESEARCH DESIGN AND METHODS A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control. RESULTS The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONS In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage. Full Article
bet Smartphone-Based Glucose Monitors and Applications in the Management of Diabetes: An Overview of 10 Salient "Apps" and a Novel Smartphone-Connected Blood Glucose Monitor By clinical.diabetesjournals.org Published On :: 2012-10-01 Joseph TranOct 1, 2012; 30:173-178Practical Pointers Full Article
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bet Mortality Implications of Prediabetes and Diabetes in Older Adults By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 OBJECTIVE Diabetes in older age is heterogeneous, and the treatment approach varies by patient characteristics. We characterized the short-term all-cause and cardiovascular mortality risk associated with hyperglycemia in older age. RESEARCH DESIGN AND METHODS We included 5,791 older adults in the Atherosclerosis Risk in Communities Study who attended visit 5 (2011–2013; ages 66–90 years). We compared prediabetes (HbA1c 5.7% to <6.5%), newly diagnosed diabetes (HbA1c ≥6.5%, prior diagnosis <1 year, or taking antihyperglycemic medications <1 year), short-duration diabetes (duration ≥1 year but <10 years [median]), and long-standing diabetes (duration ≥10 years). Outcomes were all-cause and cardiovascular mortality (median follow-up of 5.6 years). RESULTS Participants were 58% female, and 24% had prevalent cardiovascular disease. All-cause mortality rates, per 1,000 person-years, were 21.2 (95% CI 18.7, 24.1) among those without diabetes, 23.7 (95% CI 20.8, 27.1) for those with prediabetes, 33.8 (95% CI 25.2, 45.5) among those with recently diagnosed diabetes, 29.6 (95% CI 25.0, 35.1) for those with diabetes of short duration, and 48.6 (95% CI 42.4, 55.7) for those with long-standing diabetes. Cardiovascular mortality rates, per 1,000 person-years, were 5.8 (95% CI 4.6, 7.4) among those without diabetes, 6.6 (95% CI 5.2, 8.5) for those with prediabetes, 11.5 (95% CI 7.0, 19.1) among those with recently diagnosed diabetes, 8.2 (95% CI 5.9, 11.3) for those with diabetes of short duration, and 17.3 (95% CI 13.8, 21.7) for those with long-standing diabetes. After adjustment for other cardiovascular risk factors, prediabetes and newly diagnosed diabetes were not significantly associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.03 [95% CI 0.85, 1.23] and HR 1.31 [95% CI 0.94, 1.82], respectively) or cardiovascular mortality (HR 1.00 [95% CI 0.70, 1.43] and HR 1.35 [95% CI 0.74, 2.49], respectively). Excess mortality risk was primarily concentrated among those with long-standing diabetes (all-cause: HR 1.71 [95% CI 1.40, 2.10]; cardiovascular: HR 1.72 [95% CI 1.18, 2.51]). CONCLUSIONS In older adults, long-standing diabetes has a substantial and independent effect on short-term mortality. Older individuals with prediabetes remained at low mortality risk over a median 5.6 years of follow-up. Full Article
bet Within-Trial Evaluation of Medical Resources, Costs, and Quality of Life Among Patients With Type 2 Diabetes Participating in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 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. Full Article
bet Plasma Lipidome and Prediction of Type 2 Diabetes in the Population-Based Malmö Diet and Cancer Cohort By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 OBJECTIVE Type 2 diabetes mellitus (T2DM) is associated with dyslipidemia, but the detailed alterations in lipid species preceding the disease are largely unknown. We aimed to identify plasma lipids associated with development of T2DM and investigate their associations with lifestyle. RESEARCH DESIGN AND METHODS At baseline, 178 lipids were measured by mass spectrometry in 3,668 participants without diabetes from the Malmö Diet and Cancer Study. The population was randomly split into discovery (n = 1,868, including 257 incident cases) and replication (n = 1,800, including 249 incident cases) sets. We used orthogonal projections to latent structures discriminant analyses, extracted a predictive component for T2DM incidence (lipid-PCDM), and assessed its association with T2DM incidence using Cox regression and lifestyle factors using general linear models. RESULTS A T2DM-predictive lipid-PCDM derived from the discovery set was independently associated with T2DM incidence in the replication set, with hazard ratio (HR) among subjects in the fifth versus first quintile of lipid-PCDM of 3.7 (95% CI 2.2–6.5). In comparison, the HR of T2DM among obese versus normal weight subjects was 1.8 (95% CI 1.2–2.6). Clinical lipids did not improve T2DM risk prediction, but adding the lipid-PCDM to all conventional T2DM risk factors increased the area under the receiver operating characteristics curve by 3%. The lipid-PCDM was also associated with a dietary risk score for T2DM incidence and lower level of physical activity. CONCLUSIONS A lifestyle-related lipidomic profile strongly predicts T2DM development beyond current risk factors. Further studies are warranted to test if lifestyle interventions modifying this lipidomic profile can prevent T2DM. Full Article