Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-39209205

RESUMO

Clinical practice guidelines can facilitate diagnosis and management of patients with metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction associated steatohepatitis (MASH), although their implementation to date has been suboptimal.1,2 Using recently published 2023 American Association for the Study of Liver Diseases (AASLD) practice guidance-based recommendations as a reference,3 we assessed current real-world management of patients with MASH to identify gaps in clinical practice. We extracted data from the Adelphi Real World MASH Disease Specific Programme, a cross-sectional survey with retrospective data capture (from 85 hepatologists, gastroenterologists, and endocrinologists [Supplementary Table 1] and 633 patients [Supplementary Table 2] in the United States between January and June 2022). Two key goals of the AASLD guidance algorithm served as reference points: exclude fibrosis in low-prevalence populations (Goal A) and identify/manage people with 'at-risk' MASH or cirrhosis (Goal B).3 Patients were split into 2 groups: Goal A comprised 100 patients initially diagnosed by primary care physicians (PCPs)/endocrinologists, and Goal B included 533 patients managed by gastroenterologists/hepatologists.

2.
Am J Hum Genet ; 104(1): 45-54, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609407

RESUMO

Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two ADAMTS9 mutations (c.4575_4576del [p.Gln1525Hisfs∗60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of Adamts9 in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of adamts9 in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in ADAMTS9 cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.


Assuntos
Proteína ADAMTS9/genética , Ciliopatias/genética , Mutação , Doenças Renais Policísticas/genética , Proteína ADAMTS9/metabolismo , Animais , Cílios/patologia , Ciliopatias/patologia , Feminino , Humanos , Masculino , Fenótipo , Doenças Renais Policísticas/patologia , Esferoides Celulares , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
3.
J Am Soc Nephrol ; 31(6): 1191-1211, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32381600

RESUMO

BACKGROUND: Mutations in ADCK4 (aarF domain containing kinase 4) generally manifest as steroid-resistant nephrotic syndrome and induce coenzyme Q10 (CoQ10) deficiency. However, the molecular mechanisms underlying steroid-resistant nephrotic syndrome resulting from ADCK4 mutations are not well understood, largely because the function of ADCK4 remains unknown. METHODS: To elucidate the ADCK4's function in podocytes, we generated a podocyte-specific, Adck4-knockout mouse model and a human podocyte cell line featuring knockout of ADCK4. These knockout mice and podocytes were then treated with 2,4-dihydroxybenzoic acid (2,4-diHB), a CoQ10 precursor analogue, or with a vehicle only. We also performed proteomic mass spectrometry analysis to further elucidate ADCK4's function. RESULTS: Absence of Adck4 in mouse podocytes caused FSGS and albuminuria, recapitulating features of nephrotic syndrome caused by ADCK4 mutations. In vitro studies revealed that ADCK4-knockout podocytes had significantly reduced CoQ10 concentration, respiratory chain activity, and mitochondrial potential, and subsequently displayed an increase in the number of dysmorphic mitochondria. However, treatment of 3-month-old knockout mice or ADCK4-knockout cells with 2,4-diHB prevented the development of renal dysfunction and reversed mitochondrial dysfunction in podocytes. Moreover, ADCK4 interacted with mitochondrial proteins such as COQ5, as well as cytoplasmic proteins such as myosin and heat shock proteins. Thus, ADCK4 knockout decreased the COQ complex level, but overexpression of ADCK4 in ADCK4-knockout podocytes transfected with wild-type ADCK4 rescued the COQ5 level. CONCLUSIONS: Our study shows that ADCK4 is required for CoQ10 biosynthesis and mitochondrial function in podocytes, and suggests that ADCK4 in podocytes stabilizes proteins in complex Q in podocytes. Our study also suggests a potential treatment strategy for nephrotic syndrome resulting from ADCK4 mutations.


Assuntos
Hidroxibenzoatos/farmacologia , Proteínas Quinases/fisiologia , Ubiquinona/análogos & derivados , Animais , Estabilidade Enzimática , Glomerulosclerose Segmentar e Focal/etiologia , Células HEK293 , Humanos , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Proteínas Mitocondriais/metabolismo , Podócitos/enzimologia , Ubiquinona/metabolismo
4.
J Am Soc Nephrol ; 30(3): 393-405, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30737270

RESUMO

BACKGROUND: Although studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also called CoQ10, CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function. METHODS: To study COQ6 function in podocytes, we generated a podocyte-specific Coq6 knockout mouse (Coq6podKO ) model and a transient siRNA-based COQ6 knockdown in a human podocyte cell line. Mice were monitored for development of proteinuria and assessed for development of glomerular sclerosis. Using a podocyte migration assay, we compared motility in COQ6 knockdown podocytes and control podocytes. We also randomly assigned 5-month-old Coq6podKO mice and controls to receive no treatment or 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of a CoQ precursor molecule that is classified as a food additive by health authorities in Europe and the United States. RESULTS: Abrogation of Coq6 in mouse podocytes caused FSGS and proteinuria (>46-fold increases in albuminuria). In vitro studies revealed an impaired podocyte migration rate in COQ6 knockdown human podocytes. Treating Coq6podKO mice or cells with 2,4-diHB prevented renal dysfunction and reversed podocyte migration rate impairment. Survival of Coq6podKO mice given 2,4diHB was comparable to that of control mice and significantly higher than that of untreated Coq6podKO mice, half of which died by 10 months of age. CONCLUSIONS: These findings reveal a potential novel treatment strategy for those cases of human nephrotic syndrome that are caused by a primary dysfunction in the CoQ10 biosynthesis pathway.

5.
Nephrol Dial Transplant ; 34(3): 485-493, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29534211

RESUMO

BACKGROUND: Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ∼15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ∼30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-α5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. METHODS: To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. RESULTS: In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. CONCLUSION: We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.


Assuntos
Sequenciamento do Exoma/métodos , Imunossupressores/uso terapêutico , Laminina/genética , Mutação , Síndrome Nefrótica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/patologia , Linhagem , Fenótipo , Prognóstico , Adulto Jovem
6.
Nephrol Dial Transplant ; 34(3): 474-485, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295827

RESUMO

BACKGROUND: Alport syndrome (AS) and atypical hemolytic-uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. METHODS: We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. RESULTS: We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). CONCLUSIONS: We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.


Assuntos
Sequenciamento do Exoma/métodos , Marcadores Genéticos , Mutação , Nefrite/diagnóstico , Nefrite/genética , Nefrose/diagnóstico , Nefrose/genética , Adolescente , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/genética , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Prognóstico
7.
J Am Soc Nephrol ; 29(8): 2123-2138, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29959197

RESUMO

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS. METHODS: To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the in vitro functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like Drosophila nephrocytes. RESULTS: We identified conserved, homozygous missense mutations of GAPVD1 in two families with early-onset NS and a homozygous missense mutation of ANKFY1 in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of GAPVD1 or ANKFY1 bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived GAPVD1 mutations reduced nephrin-GAPVD1 binding affinity. In Drosophila, silencing Gapvd1 impaired endocytosis and caused mistrafficking of the nephrin ortholog. CONCLUSIONS: Mutations in GAPVD1 and probably in ANKFY1 are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.


Assuntos
Regulação da Expressão Gênica , Proteínas de Membrana/genética , Síndrome Nefrótica/genética , Podócitos/metabolismo , Proteínas rab5 de Ligação ao GTP/genética , Animais , Movimento Celular/genética , Células Cultivadas , Estudos de Coortes , Progressão da Doença , Drosophila melanogaster , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Programas de Rastreamento/métodos , Mutação de Sentido Incorreto , Síndrome Nefrótica/patologia , Linhagem , Proteínas de Ligação a Fosfato , Podócitos/patologia , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Sequenciamento do Exoma
8.
J Am Soc Nephrol ; 29(9): 2348-2361, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30143558

RESUMO

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.


Assuntos
Sequenciamento do Exoma/métodos , Predisposição Genética para Doença/epidemiologia , Linhagem , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Animais , Humanos , Incidência , Rim/anormalidades , Camundongos , Fenótipo , Prognóstico , Medição de Risco , Sensibilidade e Especificidade , Distribuição por Sexo , Sistema Urinário/anormalidades , Anormalidades Urogenitais/epidemiologia , Refluxo Vesicoureteral/epidemiologia
9.
Kidney Int ; 93(1): 204-213, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28893421

RESUMO

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.


Assuntos
Sequenciamento do Exoma , Mutação , Nefrocalcinose/genética , Nefrolitíase/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Progressão da Doença , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Humanos , Lactente , Masculino , Nefrocalcinose/diagnóstico por imagem , Nefrocalcinose/epidemiologia , Nefrolitíase/diagnóstico por imagem , Nefrolitíase/epidemiologia , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Tomografia Computadorizada por Raios X , Ultrassonografia , Adulto Jovem
10.
Am J Med Genet A ; 176(11): 2460-2465, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30079490

RESUMO

Galloway-Mowat syndrome (GAMOS) is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease, manifesting with proteinuria. To identify additional monogenic disease causes, we here performed whole exome sequencing (WES), linkage analysis, and homozygosity mapping in three affected siblings of an Indian family with GAMOS. Applying established criteria for variant filtering, we identify a novel homozygous splice site mutation in the gene WDR4 as the likely disease-causing mutation in this family. In line with previous reports, we observe growth deficiency, microcephaly, developmental delay, and intellectual disability as phenotypic features resulting from WDR4 mutations. However, the newly identified allele additionally gives rise to proteinuria and nephrotic syndrome, a phenotype that was never reported in patients with WDR4 mutations. Our data thus expand the phenotypic spectrum of WDR4 mutations by demonstrating that, depending on the specific mutated allele, a renal phenotype may be present. This finding suggests that GAMOS may occupy a phenotypic spectrum with other microcephalic diseases. Furthermore, WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to GAMOS, if mutated. Our findings thereby support the recent observation that, like neurons, podocytes of the renal glomerulus are particularly vulnerable to cellular defects resulting from altered tRNA modifications.


Assuntos
Proteínas de Ligação ao GTP/genética , Hérnia Hiatal/genética , Microcefalia/genética , Mutação , Nefrose/genética , Adolescente , Criança , Pré-Escolar , Genes Recessivos , Humanos , Sequenciamento do Exoma
11.
Pediatr Nephrol ; 33(2): 305-314, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28921387

RESUMO

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of end-stage renal disease (ESRD) among patients manifesting at under 25 years of age. We performed mutation analysis using a high-throughput PCR-based microfluidic technology in 24 single-gene causes of SRNS in a cohort of 72 families, who presented with SRNS before the age of 25 years. METHODS: Within an 18-month interval, we obtained DNA samples, pedigree information, and clinical information from 77 consecutive children with SRNS from 72 different families seen at Boston Children's Hospital (BCH). Mutation analysis was completed by combining high-throughput multiplex PCR with next-generation sequencing. We analyzed the sequences of 18 recessive and 6 dominant genes of SRNS in all 72 families for disease-causing variants. RESULTS: We identified the disease-causing mutation in 8 out of 72 (11.1%) families. Mutations were detected in the six genes: NPHS1 (2 out of 72), WT1 (2 out of 72), NPHS2, MYO1E, TRPC6, and INF2. Median age at onset was 4.1 years in patients without a mutation (range 0.5-18.8), and 3.2 years in those in whom the causative mutation was detected (range 0.1-14.3). Mutations in dominant genes presented with a median onset of 4.5 years (range 3.2-14.3). Mutations in recessive genes presented with a median onset of 0.5 years (range 0.1-3.2). CONCLUSION: Our molecular genetic diagnostic study identified underlying monogenic causes of steroid-resistant nephrotic syndrome in ~11% of patients with SRNS using a cost-effective technique. We delineated some of the therapeutic, diagnostic, and prognostic implications. Our study confirms that genetic testing is indicated in pediatric patients with SRNS.


Assuntos
Predisposição Genética para Doença/genética , Síndrome Nefrótica/congênito , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Síndrome Nefrótica/genética
12.
Diabetes Ther ; 15(2): 409-426, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38038898

RESUMO

INTRODUCTION: Weight loss has been identified as a key strategy for improving glycemic and metabolic outcomes in people with type 2 diabetes (T2D). However, the long-term, real-world impact of weight loss on these outcomes remains unclear. This study aimed to investigate (1) the association between weight loss and glycemic control, (2) association between weight loss and metabolic parameters, and (3) predictors of weight loss and how weight change trajectory varies based on index body mass index (BMI). METHODS: A retrospective, longitudinal cohort study using the linked IQVIA Ambulatory electronic medical records and PharMetrics® Plus databases was performed from January 1, 2010 through December 31, 2019 in adults with T2D. Participants were categorized into 1-year and 5-year follow-up cohorts based on their observed weight change over time. Longitudinal values for vital signs and laboratory parameters, including BMI, weight, glycated hemoglobin (HbA1c), and metabolic parameters (liver enzymes and cholesterol), were reported at index date and every 6 months post index date. Multivariable logistic regression analysis was used to evaluate the factors associated with weight loss. RESULTS: Of 1,493,964 people evaluated, 1,061,354 (71%) and 308,320 (20.6%) were classified into the 1-year and 5-year follow-up cohorts. Average HbA1c reductions of 1.2% and 0.5% were observed among people who lost ≥ 15% of index weight in the 1-year and 5-year follow-up cohorts, respectively. Higher weight loss percentages were associated with numerically greater improvements in metabolic parameters. The presence of bariatric surgery and higher index BMIs were identified as the strongest predictors of ≥ 15% and ≥ 10% weight loss in both follow-up cohorts. CONCLUSION: Results from this study suggest that modest and sustained weight loss can lead to clinically meaningful improvements in glycemic and metabolic parameters among people with T2D. These findings highlight the importance of weight management in managing T2D and preventing its associated complications.

13.
Diabetes Ther ; 15(11): 2367-2379, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39347898

RESUMO

INTRODUCTION: Daily insulin administration can be burdensome for people with type 2 diabetes (PwT2D) and can impact treatment adherence. This study investigated preferences for once-weekly, long-acting basal insulin for treatment of PwT2D. METHODS: An online discrete-choice experiment was administered to PwT2D in the USA. Qualitative interviews informed the selection of six attributes: reduction in A1c level after 6 months, amount of time spent in optimal blood sugar range each day, number of serious low blood sugar events, number of nighttime low blood sugar events, change in weight because of the insulin over 6 months, and frequency of administration. Each participant completed eight questions offering a choice between two long-acting insulins; questions varied according to an experimental design. A fixed treatment choice question asked about preferences for daily versus weekly insulin, holding other treatment features constant. Data were analyzed using random-parameters logit models, and heterogeneity was explored through subgroup analyses. RESULTS: Four hundred sixty-six PwT2D completed the survey (mean age, 57; mean A1c, 7.5%; 59.0% female); 33.3% of these were currently on a basal/bolus regimen, 34.3% used basal only, and 32.4% were insulin naive. Respondents placed the most importance on avoiding a 10-pound weight change and equal importance on the largest change in the number of serious and nighttime low blood sugar events per year and achieving the longest time in range included in the choice questions. There was significant heterogeneity in preferences by experience: insulin-naive respondents had stronger preferences for scheduled and flexible weekly insulin over daily insulin; 67.6% preferred flexible weekly over daily insulin, all else being equal. CONCLUSION: PwT2D valued insulin efficacy and reducing treatment-related adverse events, with heterogeneity in the relative importance of administration frequency. All else being equal, respondents preferred weekly over daily basal insulin. These findings provide insights into the preferences of PwT2D considering weekly long-acting insulin.

14.
Diabetes Ther ; 14(6): 967-975, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37067668

RESUMO

INTRODUCTION: Glycated hemoglobin A1c (HbA1c) is an important measure to assess glycemic control and predict diabetes complications. However, there is limited information on trends in HbA1c among people with diabetes (PwDs) who use insulin. The aim of this study was to describe trends in HbA1c among PwDs who use insulin by diabetes type and insulin regimen. METHODS: A retrospective analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES, 2009-2020). PwDs were classified into three cohorts: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus using mealtime insulin (T2DM-MTI), and type 2 diabetes mellitus (T2DM) using basal-only insulin (T2DM basal-only). Trends in HbA1c over time were assessed using regression analysis after adjusting for age, gender, and race/ethnicity. RESULTS: Mean HbA1c values aggregated over 2009-2020 were 8.0% (T1DM), 8.6% (T2DM-MTI), and 8.6% (T2DM basal-only). The American Diabetes Association-recommended target of HbA1c of < 7% was achieved by 25.2% of people in the T1DM and T2DM-MTI groups each and by 12.3% of people in the T2DM basal-only group. Over time, an upward trend was observed in the percentage of people achieving HbA1c < 7% in the T2DM basal-only group. The percentage of PwDs achieving individualized HbA1c targets was 27.0%, 12.4%, and 16.1% for the T1DM, T2DM-MTI, and T2DM basal-only groups, respectively. CONCLUSIONS: Our study using NHANES data suggests that approximately 25% of PwDs achieve glycemic targets. This study highlights the need for improved therapies to better manage glycemic targets in PwDs.

15.
Diabetes Ther ; 14(7): 1157-1174, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37184630

RESUMO

INTRODUCTION: Basal insulin's position in the type 2 diabetes (T2D) treatment paradigm has undergone significant revisions since the advent of diabetes medications such as glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), which offer cardiorenal protection for people with T2D (PwT2D). This study aimed to characterize the demographic, clinical, and diabetes medication utilization patterns of PwT2D initiating basal insulin between 2014 and 2020 over the time period when these revisions were occurring. METHODS: A retrospective study was conducted using the IBM® MarketScan® databases and included adults with T2D who initiated basal insulin therapy (basal insulin initiators) in 2015, 2017, or 2019. Patient characteristics, medication utilization patterns, and time to add an additional diabetes drug class were compared across years. Characteristics of users of basal insulin-GLP-1RA combination therapy (GLP-1RA-basal insulin dual users) were also compared across years. RESULTS: Between 2015 and 2019, initiation of basal insulin therapy remained steady, with 1.6-1.9% of PwT2D starting basal insulin in each year. GLP-1RA and SGLT-2i use increased pre- and post-basal insulin initiation (pre-basal: GLP-1RA, from 14.8% to 25.2%, p < 0.0001; SGLT-2i, from 11.4% to 20.5%, p < 0.0001; post-basal: GLP-1RA, from 16.7% to 30.5%, p < 0.0001; SGLT-2i, from 13.4% to 23.3%, p < 0.0001]). The proportion of PwT2D with underlying cardiovascular and renal diseases did not increase during this period. Among basal insulin initiators without prior GLP-1RA, SGLT-2i, or bolus insulin use, time to adding on these agents decreased, with 14.0-15.6% starting bolus insulin within the first year. Among GLP-1RA-basal insulin dual initiators, the proportion of those with underlying cardiovascular disease was not higher among GLP-1RA first users. CONCLUSIONS: In this real-world study, insulin remained key in the T2D treatment paradigm. A growing proportion of PwT2D utilized GLP-1RAs and SGLT-2is before and after initiation of basal insulin therapy. At the same time, there was no increase in the proportion of those initiating basal insulin who had cardiorenal comorbidity profiles for which treatment guidelines have recommended the use of GLP-1RAs or SGLT-2is.

16.
PLoS One ; 13(1): e0191503, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29346415

RESUMO

Until recently, morpholino oligonucleotides have been widely employed in zebrafish as an acute and efficient loss-of-function assay. However, off-target effects and reproducibility issues when compared to stable knockout lines have compromised their further use. Here we employed an acute CRISPR/Cas approach using multiple single guide RNAs targeting simultaneously different positions in two exemplar genes (osgep or tprkb) to increase the likelihood of generating mutations on both alleles in the injected F0 generation and to achieve a similar effect as morpholinos but with the reproducibility of stable lines. This multi single guide RNA approach resulted in median likelihoods for at least one mutation on each allele of >99% and sgRNA specific insertion/deletion profiles as revealed by deep-sequencing. Immunoblot showed a significant reduction for Osgep and Tprkb proteins. For both genes, the acute multi-sgRNA knockout recapitulated the microcephaly phenotype and reduction in survival that we observed previously in stable knockout lines, though milder in the acute multi-sgRNA knockout. Finally, we quantify the degree of mutagenesis by deep sequencing, and provide a mathematical model to quantitate the chance for a biallelic loss-of-function mutation. Our findings can be generalized to acute and stable CRISPR/Cas targeting for any zebrafish gene of interest.


Assuntos
Técnicas de Silenciamento de Genes , Microcefalia/genética , Modelos Biológicos , RNA/genética , Peixe-Zebra/genética , Animais , Sistemas CRISPR-Cas , Sequenciamento de Nucleotídeos em Larga Escala , Mutação INDEL , Mutagênese , Fenótipo
17.
Nat Commun ; 9(1): 1960, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29773874

RESUMO

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.


Assuntos
Resistência a Medicamentos/genética , Glucocorticoides/farmacologia , Síndrome Nefrótica/tratamento farmacológico , Mapas de Interação de Proteínas/genética , Proteína rhoA de Ligação ao GTP/genética , Adulto , Animais , Criança , Pré-Escolar , Análise Mutacional de DNA , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Glucocorticoides/uso terapêutico , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mutação , Síndrome Nefrótica/genética , Linhagem , Podócitos , RNA Interferente Pequeno/metabolismo , Resultado do Tratamento , Sequenciamento do Exoma , Proteína rhoA de Ligação ao GTP/metabolismo
18.
J Clin Invest ; 128(10): 4313-4328, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30179222

RESUMO

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.


Assuntos
Síndrome Nefrótica/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Xenopus/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Síndrome Nefrótica/genética , Síndrome Nefrótica/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Xenopus/genética , Xenopus laevis , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
19.
Clin J Am Soc Nephrol ; 13(1): 53-62, 2018 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-29127259

RESUMO

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS: In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.


Assuntos
Análise Mutacional de DNA/métodos , Sequenciamento do Exoma , Marcadores Genéticos , Mutação , Síndrome Nefrótica/congênito , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Humanos , Lactente , Masculino , Taxa de Mutação , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/epidemiologia , Síndrome Nefrótica/genética , Síndrome Nefrótica/terapia , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Adulto Jovem
20.
J Clin Invest ; 127(12): 4257-4269, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29058690

RESUMO

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein.


Assuntos
Proteínas dos Microfilamentos , Mutação , Síndrome Nefrótica/congênito , Fosfoinositídeo Fosfolipase C , Podócitos , Pseudópodes , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Movimento Celular/genética , Diglicerídeos/genética , Diglicerídeos/metabolismo , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Síndrome Nefrótica/genética , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Fosfoinositídeo Fosfolipase C/genética , Fosfoinositídeo Fosfolipase C/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Pseudópodes/genética , Pseudópodes/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA