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People with diabetes often encounter stigma (ie, negative social judgments, stereotypes, prejudice), which can adversely affect emotional, mental, and physical health; self-care, access to optimal health care; and social and professional opportunities. To accelerate an end to diabetes stigma and discrimination, an international multidisciplinary expert panel (n=51 members, from 18 countries) conducted rapid reviews and participated in a three-round Delphi survey process. We achieved consensus on 25 statements of evidence and 24 statements of recommendations. The consensus is that diabetes stigma is driven primarily by blame, perceptions of burden or sickness, invisibility, and fear or disgust. On average, four in five adults with diabetes experience diabetes stigma and one in five experience discrimination (ie, unfair and prejudicial treatment) due to diabetes, such as in health care, education, and employment. Diabetes stigma and discrimination are harmful, unacceptable, unethical, and counterproductive. Collective leadership is needed to proactively challenge, and bring an end to, diabetes stigma and discrimination. Consequently, we achieved unanimous consensus on a pledge to end diabetes stigma and discrimination.
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Diabetes Mellitus , Estigma Social , Adulto , Humanos , Prejuicio , Atención a la Salud , Encuestas y Cuestionarios , Diabetes Mellitus/terapiaRESUMEN
Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.
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Cromosomas Humanos Par 21 , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Cromosomas Humanos Par 21/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Aberraciones Cromosómicas , Citogenética , Genómica , Factor 1 de Ensamblaje de la Cromatina/genéticaRESUMEN
OBJECTIVE: One of the most frequently occurring complications of diabetes mellitus is peripheral neuropathy. Despite the painful symptoms associated with diabetic peripheral neuropathy (DPN), the current treatment landscape focuses on managing symptoms without addressing the underlying causes of DPN. This narrative review describes the mechanistic effects and clinical trial data supporting the use of L-methylfolate calcium (LMF), the bioactive form of folate, which is available in the United States as a prescription medical food that also contains other B vitamins for the dietary management of DPN. METHODS: Preclinical and clinical trial data evaluating the impact of LMF on DPN were identified using PubMed searches for articles published between 2010 and 2023. Search terms included: folate, LMF, diabetes, neuropathy, and neuropathic pain. Additionally, a literature search was conducted to identify studies related to LMF, genetic polymorphisms, and DPN pathophysiology. RESULTS: Several studies show that the C677T variant of the methylenetetrahydrofolate reductase gene is linked to greater risk of DPN than other methylenetetrahydrofolate reductase variants due to its inhibitory effects on several folic acid metabolic pathways. One double-blind, randomized controlled trial, 5 open-label studies, and 1 retrospective study found that LMF has a significant beneficial effect on DPN that extends beyond symptomatic relief to include modulating the underlying pathophysiology that leads to the progression and symptoms of DPN. LMF also significantly improves patient quality of life, with minimal adverse effects. CONCLUSION: Preclinical and clinical studies have found that LMF can be used to treat the underlying causes of DPN and provide long-lasting symptomatic relief.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Calidad de Vida , Estudios Retrospectivos , Ácido Fólico/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here, we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-ß as a potential targetable pathway. Further, we observed nonrandom genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.
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Neoplasias , Proteínas Supresoras de Tumor , Ratones , Animales , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Hematopoyesis/genética , Mutación de Línea Germinal , Factores de Transcripción/genética , Deleción Cromosómica , Neoplasias/genética , Síndrome , Trastornos de Fallo de la Médula ÓseaRESUMEN
We characterized the human ß-like globin transgenes in two mouse models of sickle cell disease (SCD) and tested a genome-editing strategy to induce red blood cell fetal hemoglobin (HbF; α2γ2). Berkeley SCD mice contain four to 22 randomly arranged, fragmented copies of three human transgenes (HBA1, HBG2-HBG1-HBD-HBBS and a mini-locus control region) integrated into a single site of mouse chromosome 1. Cas9 disruption of the BCL11A repressor binding motif in the γ-globin gene (HBG1 and HBG2; HBG) promoters of Berkeley mouse hematopoietic stem cells (HSCs) caused extensive death from multiple double-strand DNA breaks. Long-range sequencing of Townes SCD mice verified that the endogenous Hbb genes were replaced by single-copy segments of human HBG1 and HBBS including proximal but not some distal gene-regulatory elements. Townes mouse HSCs were viable after Cas9 disruption of the HBG1 BCL11A binding motif but failed to induce HbF to therapeutic levels, contrasting with human HSCs. Our findings provide practical information on the genomic structures of two common mouse SCD models, illustrate their limitations for analyzing therapies to induce HbF and confirm the importance of distal DNA elements in human globin regulation. This article has an associated First Person interview with the first author of the paper.
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Anemia de Células Falciformes , Hemoglobina Fetal , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/terapia , Animales , Modelos Animales de Enfermedad , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Edición Génica , Humanos , Ratones , Factores de Transcripción/genética , Transgenes , gamma-Globinas/genéticaRESUMEN
The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML. SIGNIFICANCE: We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171.
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Leucemia Mieloide Aguda , Adulto , Niño , Aberraciones Cromosómicas , Exones , Genómica , Humanos , Leucemia Mieloide Aguda/genética , Mutación , RecurrenciaRESUMEN
Type 2 diabetes mellitus (T2DM) affects millions of people worldwide, elevating their risk of developing a range of complications, including chronic kidney disease (CKD). People with T2DM and CKD (i.e., diabetic kidney disease, DKD) have an increased risk of progressing to end-stage kidney disease (ESKD), experiencing cardiovascular complications, and premature death. Despite this, DKD is primarily addressed through management of risk factors, and there are few pharmaceutical treatments capable of reversing or delaying disease progression. Canagliflozin is a sodium glucose co-transporter 2 inhibitor that was initially developed as a blood glucose-lowering agent for people with T2DM. Evidence from clinical trials of canagliflozin in people with T2DM, as well as evidence from cardiovascular outcomes trials in people with T2DM and high cardiovascular risk, provided preliminary evidence suggesting that it may also have beneficial renal effects. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was a dedicated renal outcomes trial of canagliflozin that assessed its renal effects in people with DKD. Overall, the CREDENCE trial demonstrated that canagliflozin improves renal outcomes and slows early disease progression in people with DKD. These data supported the approval of canagliflozin for the treatment DKD, the first new treatment in almost 20 years; therefore, it is important for clinicians to understand how to implement this treatment in their clinical practice.
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Editor's Note: This article is adapted from the address Ms. Valentine delivered as the recipient of the American Diabetes Association's (ADA's) Outstanding Educator in Diabetes Award for 2019. She delivered the address in June 2019 at the Association's 79th Scientific Sessions in San Francisco, CA. A webcast of this speech is available for viewing at the ADA website (professional.diabetes.org/webcast/outstanding-educator-diabetes-award-lecture%E2%80%94-most-important-thing-we-give-people-hope).
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Background: A room-temperature stable, soluble liquid glucagon formulation loaded into a prefilled, single-use, two-step autoinjector is under development for severe hypoglycemia rescue. We report a human factors validation program evaluating the glucagon autoinjector (GAI) (Gvoke HypoPen™; Xeris Pharmaceuticals, Inc., Chicago, IL) versus marketed glucagon emergency kits (GEKs) for managing severe hypoglycemia. Methods: A simulated-use human factors usability study was conducted with the GAI versus marketed GEKs in 16 participants, including adult caregivers and first responders, experienced with glucagon administration. A summative human factors validation study of the GAI was conducted with 75 volunteers. Participants were (1) trained on the device and procedure or (2) given time to individually read the instructions and familiarize themselves with the device. Participants returned a week later to perform an unaided rescue attempt that simulated rescue of patients with diabetes suffering a hypoglycemia emergency. Participant actions were recorded for critical rescue tasks and use errors. Results: In the usability study, 88% (14) successfully administered a rescue injection using the GAI versus 31% (5) using GEKs (P < 0.05). Mean total rescue time of use was 47.9 s with the GAI versus 109.0 s with GEKs (P < 0.05). In the validation study, 98.7% successfully administered the rescue injection using the GAI. Overall, there were no patterns of differences between trained versus untrained participants, between caregivers versus first responders or between adults versus adolescents. Conclusion: The GAI and instructional materials can be correctly, safely, and effectively used by intended user, which support continued development of the GAI as an alternative to GEKs.
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Complicaciones de la Diabetes/tratamiento farmacológico , Ergonomía , Glucagón/administración & dosificación , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Inyecciones/instrumentación , Adolescente , Adulto , Cuidadores , Complicaciones de la Diabetes/etiología , Sistemas de Liberación de Medicamentos/instrumentación , Socorristas , Femenino , Humanos , Hipoglucemia/etiología , Masculino , Adulto JovenRESUMEN
Background: Adjunct therapy can help patients with type 1 diabetes achieve glycemic goals while potentially mitigating some of the side effects of insulin. In this study, we used a patient survey to identify the unmet needs in type 1 diabetes therapy, patient views of treatment benefit-risk trade-offs, and patient preferences for the use of an adjunct therapy. Methods: A quantitative survey was sent to 2084 adults with type 1 diabetes in November 2017. "Jobs-to-be-done" and conjoint analyses were performed on survey responses to identify unmet needs and the importance of treatment-associated benefits and risks to patients. A 5-point Likert scale measured the importance and satisfaction with patients' current therapy, and with gaps relating to unmet needs. In the conjoint analysis, patients were asked to choose between "packages" of attributes of two doses of adjunct therapy (200 and 400 mg) and placebo, based on established benefits and side effects. Results: A total of 1313 patients (63%) responded. The greatest unmet needs identified were simplifying treatment, lowering/maintaining glycated hemoglobin (HbA1c), reducing mental effort, and increasing time in range (TIR). Conjoint analysis showed that reductions in body weight and TIR had the highest attribute importance (25% and 18%, respectively). The majority (93%) of patients had a preference for the adjunct therapy (either dose) over placebo. Conclusions: This survey highlights the importance of measures beyond HbA1c, such as treatment simplification and TIR, and patient preference for adjunct therapies that help address unmet needs in type 1 diabetes treatment.
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Automonitorización de la Glucosa Sanguínea/psicología , Diabetes Mellitus Tipo 1/psicología , Diabetes Mellitus Tipo 1/terapia , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Prioridad del Paciente/psicología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Necesidades , Investigación Cualitativa , Adulto JovenRESUMEN
Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.
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Leucemia Eritroblástica Aguda/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Genómica/métodos , Proteínas de Homeodominio/genética , Humanos , Lactante , Recién Nacido , Masculino , Mutación/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas Nucleares/genética , Nucleofosmina , Pronóstico , Proteína p53 Supresora de Tumor/genética , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
The progressive nature of type 2 diabetes (T2D) means that many patients will require basal insulin therapy at some point in the course of the disease due to ß-cell failure. As basal insulin primarily targets fasting plasma glucose, patients may still experience considerable postprandial glucose excursions and therefore require an additional agent to achieve good glycemic control. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide an alternative to prandial insulin, with the benefits of fewer daily injections, and a lower risk of hypoglycemia and weight gain. Two fixed-ratio combinations (FRCs) of basal insulin and a GLP-1 RA are now available in the USA and the EU: insulin glargine + lixisenatide (iGlarLixi) and insulin degludec + liraglutide (IDegLira). Titratable FRCs are suitable for most patients with T2D and can help to simplify treatment regimens into one daily injection, potentially aiding in patient adherence. The complementary modes of action of the two components target seven of the many known pathophysiologic defects in T2D. FRCs have demonstrated enhanced glycemic control compared with their constituent components alone, comparable risk of hypoglycemia compared with basal insulin alone, and better tolerability compared with the GLP-1RA component alone due to the slower titration. In this article, we discuss the advantages of FRCs over multiple daily injections, present case studies of typical patients who could benefit from FRC therapy, and outline practical considerations for the initiation of FRC therapy in clinical practice.Funding Sanofi.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Insulina de Acción Prolongada/uso terapéutico , Insulina/uso terapéutico , Terapia Combinada , Combinación de Medicamentos , Péptido 1 Similar al Glucagón/administración & dosificación , Hemoglobina Glucada/análisis , Humanos , Liraglutida/administración & dosificación , Cooperación del Paciente , Periodo Posprandial , Aumento de PesoRESUMEN
IN BRIEF As more patents on biological medicines expire, increased numbers of biologic copies, referred to as "biosimilars," will likely become available in the United States in the coming years. With greater availability and the drive for health care savings, the use of biosimilars and of "follow-on" biological products is likely to increase in routine clinical practice. Health care practitioners need to be fully aware of these products and accompanying considerations if they are to make informed decisions together with their patients.
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Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (KrasG12D). We show that partial or total ATM deficiency cooperates with KrasG12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16Ink4a and p19Arf. However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.
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Proteínas de la Ataxia Telangiectasia Mutada/deficiencia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Animales , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Daño del ADN , Modelos Animales de Enfermedad , Inestabilidad Genómica , Humanos , Hibridación Fluorescente in Situ , Ratones , Ratones Noqueados , Metástasis de la Neoplasia , Neoplasias Pancreáticas/mortalidad , Tolerancia a Radiación/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Type 2 diabetes (T2D) is a progressive disease affecting glucose regulation and a major cause of morbidity and mortality globally. Many patients are not escalated up the treatment ladder appropriately despite failing to achieve glycemic control, with barriers such as fear of hypoglycemia, weight gain, and treatment burden recognized as factors. Exogenous basal insulin is titrated to address control of fasting plasma glucose and may preserve residual ß-cell function, thus promoting a greater endogenous prandial insulin response. Native glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the gut in response to nutrient ingestion; it increases insulin secretion, inhibits glucagon secretion, and prolongs gastric emptying, thereby lowering overall food intake. As its glucose-lowering action is glucose dependent, a GLP-1 receptor agonist (GLP-1RA) achieves these benefits with a lower risk of hypoglycemia compared with other diabetes therapies. Two products, an insulin degludec/liraglutide combination (IDegLira) and an insulin glargine/lixisenatide combination (IGlarLixi), were approved for use in adults with T2D by the US Food and Drug Administration in 2016. The efficacy and safety of these two basal insulin/GLP-1RA combination products were studied in the DUAL program (NCTs 01336023, 01392573, 01676116, 01618162, 01952145, and 02298192) and the LixiLan program (NCTs 02058160 and 02058147). Compared with basal insulin, insulin/GLP-1RA fixed-ratio combinations are superior at reducing HbA1c with weight neutrality or weight loss rather than weight gain, as well as reduced hypoglycemia rates, and reduced insulin-dose requirement with IDegLira. A combination of different medications may often be required to achieve glycemic control, and fixed-ratio combination products allow such therapies to be given in simple regimens. Clinical trial data for these products highlight the great potential of these agents, not merely their efficacy and safety but also their ease of use and decreased injection burden for patients.
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OBJECTIVE: The goal of insulin therapy in type 1 diabetes (T1D) is to reduce hemoglobin A1C (A1C) to ≤7.0% (53 mmol/mol) with minimal hypoglycemia. We investigated the possibility that "insulin timing" would improve A1C without incurring severe hypoglycemia in volunteers with T1D over a 6-month observation period. METHODS: Forty healthy adult volunteers with T1D were randomly assigned for 6 months to either a control group or an insulin timing group. The primary endpoint was the difference in A1C between the two groups. As a secondary endpoint, both groups were further divided to assess the importance of the baseline A1C in determining the response to timing. The insulin timing algorithm altered the time when the meal dose of insulin was injected or infused from 30 minutes before the meal to 15 minutes after the meal, depending upon the premeal blood glucose concentration. RESULTS: An improvement in mean A1C was observed in the timing group compared with no change in the control group, but this improvement did not reach statistical significance (P>.05). In contrast, when the two groups were analyzed according to baseline A1C, the timing volunteers with baseline A1C values in the upper half (separated by the A1C median of 7.45% [57.9 mmol/mol]) of the timing group had a more robust response to timing (decline in A1C) than the upper half of the control group (P<.05). CONCLUSION: Insulin timing is a patient-centered translational approach that is safe and effective in improving A1C in individuals with T1D with an elevated A1C. ABBREVIATIONS: A1C = hemoglobin A1C ANOVA = analysis of variance CGM = continuous glucose monitoring CSII = continuous subcutaneous insulin infusion MDI = multiple daily injection T1D = type 1 diabetes.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Atención Dirigida al Paciente/métodos , Adolescente , Adulto , Anciano , Automonitorización de la Glucosa Sanguínea , Esquema de Medicación , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Sistemas de Infusión de Insulina/efectos adversos , Persona de Mediana Edad , Adulto JovenRESUMEN
IN BRIEF Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antihyperglycemic agents that lower blood glucose levels in patients with type 2 diabetes. SGLT2 inhibitors have an insulin-independent mechanism of action, acting to inhibit the reabsorption of glucose in the kidney, which leads to increases in urinary glucose excretion in individuals with elevated blood glucose levels. This article provides an overview of the role of the kidney in type 2 diabetes, describes the rationale for renal SGLT2 as a new target for glycemic control, and focuses on the clinical implications of incorporating the SGLT2 inhibitor canagliflozin into type 2 diabetes treatment regimens based on data from phase 3 studies.
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Many recurrent chromosome translocations in cancer result in the generation of fusion genes that are directly implicated in the tumorigenic process. Precise modeling of the effects of cancer fusion genes in mice has been inaccurate, as constructs of fusion genes often completely or partially lack the correct regulatory sequences. The reciprocal t(2;13)(q36.1;q14.1) in human alveolar rhabdomyosarcoma (A-RMS) creates a pathognomonic PAX3-FOXO1 fusion gene. In vivo mimicking of this translocation in mice is complicated by the fact that Pax3 and Foxo1 are in opposite orientation on their respective chromosomes, precluding formation of a functional Pax3-Foxo1 fusion via a simple translocation. To circumvent this problem, we irreversibly inverted the orientation of a 4.9 Mb syntenic fragment on chromosome 3, encompassing Foxo1, by using Cre-mediated recombination of two pairs of unrelated oppositely oriented LoxP sites situated at the borders of the syntenic region. We tested if spatial proximity of the Pax3 and Foxo1 loci in myoblasts of mice homozygous for the inversion facilitated Pax3-Foxo1 fusion gene formation upon induction of targeted CRISPR-Cas9 nuclease-induced DNA double strand breaks in Pax3 and Foxo1. Fluorescent in situ hybridization indicated that fore limb myoblasts show a higher frequency of Pax3/Foxo1 co-localization than hind limb myoblasts. Indeed, more fusion genes were generated in fore limb myoblasts via a reciprocal t(1;3), which expressed correctly spliced Pax3-Foxo1 mRNA encoding Pax3-Foxo1 fusion protein. We conclude that locus proximity facilitates chromosome translocation upon induction of DNA double strand breaks. Given that the Pax3-Foxo1 fusion gene will contain all the regulatory sequences necessary for precise regulation of its expression, we propose that CRISPR-Cas9 provides a novel means to faithfully model human diseases caused by chromosome translocation in mice.
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Proteínas de Fusión Oncogénica/genética , Factores de Transcripción Paired Box/genética , Rabdomiosarcoma Alveolar/genética , Translocación Genética/genética , Animales , Sistemas CRISPR-Cas , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Ratones , Mioblastos/metabolismo , Mioblastos/patología , ARN Mensajero/biosíntesis , Rabdomiosarcoma Alveolar/metabolismo , Rabdomiosarcoma Alveolar/patologíaRESUMEN
BACKGROUND: The masked continuous glucose monitoring system (Masked-CGMS) differs from standard CGMSs in three ways: (1) there is no feedback to the user so that no immediate regimen changes can be made; (2) it can only be worn for up to 5 days; and (3) there are no alarms to warn of hyperglycemia or hypoglycemia. Since 2008 masked-CGMS has become popular for identifying reasons that a patient's hemoglobin A1C does not correlate closely with his or her capillary blood glucose measurements. To date only one study addressing the clinical utility of Masked-CGMS for improving A1C in diabetes has been published. No studies are available specifically examining the variability and correlation of Masked-CGMS and A1C. SUBJECTS AND METHODS: We performed 156 Masked-CGMS studies (40 patients studied sequentially a maximum of four times each) in type 1 diabetes patients. We then analyzed the resulting interstitial glucose levels obtained from the Masked-CGMS compared with an A1C measurement performed within 1 week of the Masked-CGMS study. RESULTS: There was a very low correlation between the A1C and the Masked-CGMS-derived mean interstitial glucose level. This statistic did not provide sufficiently predictive information to be clinically useful for changing an individual patient's intensive insulin therapy regimen. CONCLUSIONS: Our data demonstrate that a very weak correlation exists between 5 days of masked CGMS and a concurrently measured A1C level. For the individual type 1 diabetes patient, this relationship would unlikely to be clinically useful in altering the individual's treatment regimen.