Effects of a Digital Patient Empowerment and Communication Tool on Metabolic Control in People With Type 2 Diabetes: The DeMpower Multicenter Ambispective Study.

BACKGROUND: Diabetes is a major health care problem, reaching epidemic numbers worldwide. Reducing hemoglobin A1c (HbA1c) levels to recommended targets is associated with a marked decrease in the risk of type 2 diabetes mellitus (T2DM)-related complications. The implementation of new technologies, particularly telemedicine, may be helpful to facilitate self-care and empower people with T2DM, leading to improved metabolic control of the disease. OBJECTIVE: This study aimed to analyze the effect of a home digital patient empowerment and communication tool (DeMpower App) on metabolic control in people with inadequately controlled T2DM. METHODS: The DeMpower study was multicenter with a retrospective (observational: 52 weeks of follow-up) and prospective (interventional: 52 weeks of follow-up) design that included people with T2DM, aged ≥18 and ≤80 years, with HbA1c levels ≥7.5% to ≤9.5%, receiving treatment with noninsulin antihyperglycemic agents, and able to use a smartphone app. Individuals were randomly assigned (2:1) to the DeMpower app-empowered group or control group. We describe the effect of empowerment on the proportion of patients achieving the study glycemic target, defined as HbA1c≤7.5% with a ≥0.5% reduction in HbA1c at week 24. RESULTS: Due to the COVID-19 pandemic, the study was stopped prematurely, and 50 patients (33 in the DeMpower app-empowered group and 17 in the control group) were analyzed. There was a trend toward a higher proportion of patients achieving the study glycemic target (46% vs 18%; P=.07) in the DeMpower app group that was statistically significant when the target was HbA1c≤7.5% (64% vs 24%; P=.02) or HbA1c≤8% (85% vs 53%; P=.02). The mean HbA1c was significantly reduced at week 24 (-0.81, SD 0.89 vs -0.15, SD 1.03; P=.03); trends for improvement in other cardiovascular risk factors, medication adherence, and satisfaction were observed. CONCLUSIONS: The results suggest that patient empowerment through home digital tools has a potential effect on metabolic control, which might be even more relevant during the COVID-19 pandemic and in a digital health scenario.

Potential Risk of Overtreatment in Patients with Type 2 Diabetes Aged 75 Years or Older: Data from a Population Database in Catalonia, Spain.

Aim: To assess the potential risk of overtreatment in patients with type 2 diabetes (T2DM) aged 75 years or older in primary care. Methods: Electronic health records retrieved from the SIDIAP database (Catalonia, Spain) in 2016. Variables: age, gender, body mass index, registered hypoglycemia, last HbA1c and glomerular filtration rates, and prescriptions for antidiabetic drugs. Potential overtreatment was defined as having HbA1c < 7% or HbA1c < 6.5% in older patients treated with insulin, sulfonylureas, or glinides. Results: From a total population of 138,374 T2DM patients aged 75 years or older, 123,515 had at least one HbA1c available. An HbA1c below 7.0% was present in 59.1% of patients, and below 6.5% in 37.7%. Overall, 23.0% of patients were treated with insulin, 17.8% with sulfonylureas, and 6.6% with glinides. Potential overtreatment (HbA1c < 7%) was suspected in 26.6% of patients treated with any high-risk drug, 47.8% with sulfonylureas, 43.5% with glinides, and 28.1% with insulin. Using the threshold of HbA1c < 6.5%, these figures were: 21.6%, 24.4%, 17.9%, and 12.3%, respectively. Conclusion: One in four older adults with T2DM treated with antidiabetic drugs associated with a high risk of hypoglycemia might be at risk of overtreatment. This risk is higher in those treated with sulfonylureas or glinides than with insulin.

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFß1 after myocardial infarction.

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFß1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

Prevalence and coprevalence of chronic comorbid conditions in patients with type 2 diabetes in Catalonia: a population-based cross-sectional study.

OBJECTIVES: To evaluate the prevalence and coprevalence of several chronic conditions in patients with type 2 diabetes in a Mediterranean region. DESIGN: A cross-sectional study. SETTING: Two hundred and eighty-six primary care teams of the Catalonian Health Institute (Catalonia, Spain). PARTICIPANTS: We included patients aged ≥18 years with a diagnosis of type 2 diabetes by 31 December, 2016, who were registered in the Information System for the Development of Research in primary care (SIDIAP) database. We excluded patients with a diagnosis of type 1 diabetes, gestational diabetes mellitus and any other type of diabetes. PRIMARY AND SECONDARY OUTCOME MEASURES: We collected data on diabetes-related comorbidities (ie, chronic complications, associated cardiovascular risk factors and treatment complications). Diagnoses were based on the International Classification of Diseases, 10th Revision codes recorded in the database or, for some entities, on the cut-off points for a particular test result or a specific treatment indicated for that entity. The presence and stage of chronic kidney disease (CKD) were based on the glomerular filtration rate, the CKD Epidemiology Collaboration creatinine equation and the urine albumin-to-creatinine ratio. RESULTS: A total of 373 185 patients were analysed. 82% of patients exhibited ≥2 comorbidities and 31% exhibited ≥4 comorbidities. The most frequent comorbidities were hypertension (72%), hyperlipidaemia (60%), obesity (45%), CKD (33%), chronic renal failure (CRF)(28%) and cardiovascular disease (23%). The most frequently coprevalent pairs of chronic conditions were the combination of hypertension with hyperlipidaemia (45%), obesity (35%), CKD (28%), CRF (25%) or cardiovascular disease (19%), as well as the combination of hyperlipidaemia with obesity (28%), CKD (21%), CRF (18%) or cardiovascular disease (15%); other common pairs of comorbidities were obesity/CKD, obesity/CRF, hypertension/retinopathy, hypertension/albuminuria, hypertension/urinary tract infection, CVD/CRF and CVD/CKD, which were each present in more than 10% of patients. CONCLUSION: Patients with type 2 diabetes have a high frequency of coprevalence of metabolic risk factors, cardiovascular disease and CKD and thus require an integrated management approach.

Deciphering the Dynamic Transcriptional and Post-transcriptional Networks of Macrophages in the Healthy Heart and after Myocardial Injury.

Macrophage plasticity has been studied in vitro, but transcriptional regulation upon injury is poorly understood. We generated a valuable dataset that captures transcriptional changes in the healthy heart and after myocardial injury, revealing a dynamic transcriptional landscape of macrophage activation. Partial deconvolution suggested that post-injury macrophages exhibit overlapping activation of pro-inflammatory and anti-inflammatory programs rather than aligning to canonical M1/M2 programs. Furthermore, simulated dynamics and experimental validation of a regulatory core of the underlying gene-regulatory network revealed a negative-feedback loop that limits initial inflammation via hypoxia-mediated upregulation of Il10. Our results also highlight the prominence of post-transcriptional regulation (miRNAs, mRNA decay, and lincRNAs) in attenuating the myocardial injury-induced inflammatory response. We also identified a cardiac-macrophage-specific gene signature (e.g., Egfr and Lifr) and time-specific markers for macrophage populations (e.g., Lyve1, Cd40, and Mrc1). Altogether, these data provide a core resource for deciphering the transcriptional network in cardiac macrophages in vivo.

Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages.

RATIONALE: Myocardial infarction is a major cause of adult mortality worldwide. The origin(s) of cardiac fibroblasts that constitute the postinfarct scar remain controversial, in particular the potential contribution of bone marrow lineages to activated fibroblasts within the scar. OBJECTIVE: The aim of this study was to establish the origin(s) of infarct fibroblasts using lineage tracing and bone marrow transplants and a robust marker for cardiac fibroblasts, the Collagen1a1-green fluorescent protein reporter. METHODS AND RESULTS: Using genetic lineage tracing or bone marrow transplant, we found no evidence for collagen-producing fibroblasts derived from hematopoietic or bone marrow lineages in hearts subjected to permanent left anterior descending coronary artery ligation. In fact, fibroblasts within the infarcted area were largely of epicardial origin. Intriguingly, collagen-producing fibrocytes from hematopoietic lineages were observed attached to the epicardial surface of infarcted and sham-operated hearts in which a suture was placed around the left anterior descending coronary artery. CONCLUSIONS: In this controversial field, our study demonstrated that the vast majority of infarct fibroblasts were of epicardial origin and not derived from bone marrow lineages, endothelial-to-mesenchymal transition, or blood. We also noted the presence of collagen-producing fibrocytes on the epicardial surface that resulted at least in part from the surgical procedure.

Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis.

Activation and accumulation of cardiac fibroblasts, which result in excessive extracellular matrix deposition and consequent mechanical stiffness, myocyte uncoupling, and ischemia, are key contributors to heart failure progression. Recently, endothelial-to-mesenchymal transition (EndoMT) and the recruitment of circulating hematopoietic progenitors to the heart have been reported to generate substantial numbers of cardiac fibroblasts in response to pressure overload-induced injury; therefore, these processes are widely considered to be promising therapeutic targets. Here, using multiple independent murine Cre lines and a collagen1a1-GFP fusion reporter, which specifically labels fibroblasts, we found that following pressure overload, fibroblasts were not derived from hematopoietic cells, EndoMT, or epicardial epithelial-to-mesenchymal transition. Instead, pressure overload promoted comparable proliferation and activation of two resident fibroblast lineages, including a previously described epicardial population and a population of endothelial origin. Together, these data present a paradigm for the origins of cardiac fibroblasts during development and in fibrosis. Furthermore, these data indicate that therapeutic strategies for reducing pathogenic cardiac fibroblasts should shift from targeting presumptive EndoMT or infiltrating hematopoietically derived fibroblasts, toward common pathways upregulated in two endogenous fibroblast populations.

Retinoid X receptors in macrophage biology.

Retinoid X receptors (RXRs) form a distinct and unique subclass within the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. RXRs regulate a plethora of genetic programs, including cell differentiation, the immune response, and lipid and glucose metabolism. Recent advances reveal that RXRs are important regulators of macrophages, key players in inflammatory and metabolic disorders. This review outlines the versatility of RXR action in the control of macrophage gene transcription through its heterodimerization with other NRs or through RXR homodimerization. We also highlight the potential of RXR-controlled transcriptional programs as targets for the treatment of pathologies associated with altered macrophage function, such as atherosclerosis, insulin resistance, autoimmunity, and neurodegeneration.

Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression.

The retinoid X receptor alpha (RXRalpha) plays a central role in the regulation of many intracellular receptor signaling pathways and can mediate ligand-dependent transcription by forming homodimers or heterodimers with other nuclear receptors. Although several members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression, the existence in vivo of an RXR signaling pathway in macrophages has not been established. Here, we provide evidence that RXRalpha regulates the transcription of the chemokines Ccl6 and Ccl9 in macrophages independently of heterodimeric partners. Mice lacking RXRalpha in myeloid cells exhibit reduced levels of CCL6 and CCL9, impaired recruitment of leukocytes to sites of inflammation, and lower susceptibility to sepsis. These studies demonstrate that macrophage RXRalpha plays key roles in the regulation of innate immunity and represents a potential target for immunotherapy of sepsis.