XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Hyperglycemia and Adverse Pregnancy Outcomes

Owing to the relationship between extracellular vesicles (EVs) and physiological and pathological conditions, the interest in EVs is exponentially growing. EVs hold high hopes for novel diagnostic and translational discoveries. This review provides an expert-based update of recent advances in the methods to study EVs and summarizes currently accepted considerations and recommendations from sample collection to isolation, detection, and characterization of EVs. Common misconceptions and methodological pitfalls are highlighted. Although EVs are found in all body fluids, in this review, we will focus on EVs from human blood, not only our most complex but also the most interesting body fluid for cardiovascular research.

Methodological Guidelines to Study Extracellular Vesicles.

Liquid biopsy refers to the sampling and molecular analysis of the biofluids of circulating tumor cells, extracellular vesicles, nucleic acids, and so forth. Exosomes are small extracellular vesicles with sizes between 30–150 nm. They are secreted by multivesicular bodies through exocytosis in live cells and can participate in intercellular communication due to their contents, including nucleic acids, proteins, and lipids. Herein, we investigate publication frequencies on exosomes over the past 10 years, and review recent clinical studies on liquid biopsy of exosomes in the fields of oncology, pregnancy disorders, cardiovascular diseases, and organ transplantation. We also describe the advantages of exosomes as an effective liquid biopsy tool and the progression of exosome extraction methods. Finally, we depict the commercial development of exosome research and discuss the future role of exosomes in liquid biopsy.

/pdf/application-of-exosomes-as-liquid-biopsy-in-clinical-4dw9yvenlc.pdf

Application of exosomes as liquid biopsy in clinical diagnosis.

Exosomes are nanoscale (≈30-150 nm) extracellular vesicles of endocytic origin that are shed by most types of cells and circulate in bodily fluids. Exosomes carry a specific composition of proteins, lipids, RNA, and DNA and can work as cargo to transfer this information to recipient cells. Recent studies on exosomes have shown that they play an important role in various biological processes, such as intercellular signaling, coagulation, inflammation, and cellular homeostasis. These functional roles are attributed to their ability to transfer RNA, proteins, enzymes, and lipids, thereby affecting the physiological and pathological conditions in various diseases, including cancer and neurodegenerative, infectious, and autoimmune diseases (e.g., cancer initiation, progression, and metastasis). Due to these unique characteristics, exosomes are considered promising biomarkers for the diagnosis and prognosis of various diseases via noninvasive or minimally invasive procedures. Over the last decade, a plethora of methodologies have been developed for analyzing disease-specific exosomes using optical and nonoptical tools. Here, the major biological functions, significance, and potential role of exosomes as biomarkers and therapeutics are discussed. Furthermore, an overview of the most commonly used techniques for exosome analysis, highlighting the major technical challenges and limitations of existing techniques, is presented.

Biological Functions and Current Advances in Isolation and Detection Strategies for Exosome Nanovesicles.

Although there is significant interest in elucidating the role of placenta-derived exosomes (PdEs) during pregnancy, the exosomal profile in pregnancies complicated by gestational diabetes mellitus (GDM) remains to be established. The aim of this study was to compare the gestational-age profile of PdEs in maternal plasma of GDM with normal pregnancies and to determine the effect of exosomes on cytokine release from human umbilical vein endothelial cells. A prospective cohort of patients was sampled at three time points during pregnancy for each patient (i.e., 11-14, 22-24, and 32-36 weeks' gestation). A retrospective stratified study design was used to quantify exosomes present in maternal plasma of normal (n = 13) and GDM (n = 7) pregnancies. Gestational age and pregnancy status were identified as significant factors contributing to variation in plasma exosome concentration (ANOVA, P < 0.05). Post hoc analyses established that PdE concentration increased during gestation in both normal and GDM pregnancies; however, the increase was significantly greater in GDM (∼2.2-fold, ∼1.5-fold, and ∼1.8-fold greater at each gestational age compared with normal pregnancies). Exosomes isolated from GDM pregnancies significantly increased the release of proinflammatory cytokines from endothelial cells. Although the role of exosomes during GDM remains to be fully elucidated, exosome profiles may be of diagnostic utility for screening asymptomatic populations.

/pdf/gestational-diabetes-mellitus-is-associated-with-changes-in-1e5grlq5c1.pdf

Gestational diabetes mellitus is associated with changes in the concentration and bioactivity of placenta-derived exosomes in maternal circulation across gestation

Context: There is a need to develop strategies for early prediction of patients who will develop
preeclampsia (PE) to establish preventive strategies to reduce the prevalence and severity of the
disease and their associated complications
Objective: The objective of this study was to investigate whether exosomes and their microRNA
cargo present in maternal circulation can be used as early biomarker for PE
Design, Setting, Patients, and Interventions: A retrospective stratified study design was used to
quantify total exosomes and placenta-derived exosomes present in maternal plasma of normal (n =
32 per time point) and PE (n = 15 per time point) pregnancies Exosomes present in maternal
circulation were determined by nanoparticle tracking analysis An Illumina TruSeq® Small RNA
Library Prep Kit was used to construct a small RNA library from exosomal RNA obtained from
plasma samples
Results: In presymptomatic women, who subsequently developed PE, the concentration of total
exosomes and placenta-derived exosomes in maternal plasma was significantly greater than those
observed in controls, throughout pregnancy The area under the receiver operating characteristic
curves for total exosome and placenta-derived exosome concentrations were 0745 6 0094 and
0829 6 0077, respectively In total, over 300 microRNAs were identified in exosomes across
gestation, where hsa-miR-486-1-5p and hsa-miR-486-2-5p were identified as the candidate
microRNAs
Conclusions: Although the role of exosomes during PE remains to be fully elucidated, we suggest
that the concentration and content of exosomes may be of diagnostic utility for women at risk for
developing PE

/pdf/placental-exosomes-as-early-biomarker-of-preeclampsia-3dw81lk0ei.pdf

Placental Exosomes as Early Biomarker of Preeclampsia: Potential Role of Exosomal MicroRNAs Across Gestation.

Preeclampsia (PE) is one of the main causes of maternal and fetal morbidity and mortality in the world, causing nearly 40% of births delivered before 35 weeks of gestation. PE begins with inadequate trophoblast invasion early in pregnancy, which produces an increase in oxidative stress contributing to the development of systemic endothelial dysfunction in the later phases of the disease, leading to the characteristic clinical manifestation of PE. Numerous methods have been used to predict the onset of PE with different degrees of efficiency. These methods have used fetal/placental and maternal markers in different stages of pregnancy. From an epidemiological point of view, many studies have shown that PE is a disease with a strong familiar predisposition, which also varies according to geographical, socioeconomic, and racial features, and this information can be used in the prediction process. Large amounts of research have shown a genetic association with a multifactorial polygenic inheritance in the development of this disease. Many biological candidate genes and polymorphisms have been examined in their relation with PE. We will discuss the most important of them, grouped by the different pathogenic mechanisms involved in PE.

/pdf/pathogenesis-of-preeclampsia-the-genetic-component-16zqs2fpgi.pdf

Pathogenesis of Preeclampsia: The Genetic Component

Hypertensive disorders are a major cause of maternal death. Preeclampsia (PE) affects about 5% of pregnancies and is associated to high cardiovascular death risk. Understanding of its origin and cause is difficult and many etiologies have been proposed. So far, little can be done for real prevention and the only treatment is pregnancy interruption, increasing the child's risk for prematurity complications. Early markers of disease are a promising path for understanding the pathogenesis and developing new strategies for prediction and eventually disease prevention.

Etiopathogenesis, prediction, and prevention of preeclampsia.

Gestational diabetes (GD), defined as carbohydrate intolerance with onset or first recognition during pregnancy, has a prevalence of 7% and is a growing problem worldwide. Infants born to mothers with GD are more likely to be large for gestational age, incur traumatic birth injury, require a stay in the intensive care unit and develop postnatal metabolic disturbances. As the worldwide epidemic of obesity worsens, more women are entering pregnancy with metabolic alterations and preexisting insulin resistance, which is heightened by the hormonal milieu of pregnancy. The Hyperglycemia Adverse Pregnancy Outcome (HAPO) study has clearly shown that GD-related complications correlate with glycemic control. We will review the current understanding of the physiology of GD and the screening and treatment guidelines that are commonly utilized in clinical care. In addition, we will discuss the need for development of multiparametric models combining maternal clinical risk factors and biomarkers early in pregnancy to better stratify and predict risk of GD-related complications and offer targeted intervention.

Paula Correa

Papers

Gestational diabetes mellitus is associated with changes in the concentration and bioactivity of placenta-derived exosomes in maternal circulation across gestation

Placental Exosomes as Early Biomarker of Preeclampsia: Potential Role of Exosomal MicroRNAs Across Gestation.

Pathogenesis of Preeclampsia: The Genetic Component

Etiopathogenesis, prediction, and prevention of preeclampsia.

Prediction of gestational diabetes early in pregnancy: targeting the long-term complications.