RESUMO
BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-ß dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 × 10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
Assuntos
17-Hidroxiesteroide Desidrogenases/genética , 17-Hidroxiesteroide Desidrogenases/metabolismo , Nefropatias Diabéticas/genética , Falência Renal Crônica/genética , Adulto , Animais , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/metabolismo , Progressão da Doença , Exoma , Feminino , Expressão Gênica , Variação Genética , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/metabolismo , Túbulos Renais Proximais/enzimologia , Masculino , Camundongos , Pessoa de Meia-Idade , Elementos Estruturais de Proteínas/genética , Traumatismo por Reperfusão/complicações , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
RATIONALE & OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN: Post hoc analysis of blood samples. SETTING & PARTICIPANTS: 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE: Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES: Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS: In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS: Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS: A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.
Assuntos
Angiotensina II/administração & dosagem , Diabetes Mellitus Tipo 1/fisiopatologia , Hemodinâmica/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Adolescente , Adulto , Fatores Etários , Idoso , Canadá , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologia , Adulto JovemRESUMO
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Iduronidase/genética , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/genética , Mutação , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Genótipo , Saúde Global , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mucopolissacaridose I/epidemiologia , Fenótipo , Sistema de Registros , Índice de Gravidade de Doença , Adulto JovemRESUMO
AIMS: To examine the relationship between normal plasma uric acid (PUA) levels, renal haemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of type 1 diabetes (T1D) durations in adolescents, young adults and older adults. MATERIALS AND METHODS: PUA, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), and plasma renin and aldosterone were measured during a euglycaemic clamp in people with T1D: 27 adolescents (mean ± SD age 16.8 ± 1.9 years), 52 young adults (mean ± SD age 25.6 ± 5.5 years) and 66 older adults (mean ± SD age 65.7 ± 7.5 years). RESULTS: PUA was highest in patients with the longest T1D duration: 197 ± 44 µmol/L in adolescents versus 264 ± 82 µmol/L in older adults (P < 0.001). Higher PUA correlated with lower GFR only in older adults, even after correcting for age, glycated haemoglobin and sex (ß = -2.12 ± 0.56; P = 0.0003), but not in adolescents or young adults. Higher PUA correlated with lower carotid AIx (ß = -1.90, P = 0.02) in adolescents. In contrast, PUA correlated with higher cfPWV (P = 0.02) and higher plasma renin (P = 0.01) in older adults with T1D. CONCLUSIONS: The relationship between higher PUA with lower GFR, increased arterial stiffness and renin angiotensin aldosterone system (RAAS) activation was observed only in older adults with longstanding T1D. T1D duration may modify the association between PUA, renal haemodynamic function and RAAS activation, leading to renal vasoconstriction and ischaemia. Further work must determine whether pharmacological PUA-lowering prevents or reverses injurious haemodynamic and neurohormonal sequelae of longstanding T1D, thereby improving clinical outcomes.
Assuntos
Diabetes Mellitus Tipo 1 , Rim , Ácido Úrico/sangue , Rigidez Vascular/fisiologia , Adolescente , Adulto , Fatores Etários , Idoso , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Taxa de Filtração Glomerular/fisiologia , Hemodinâmica/fisiologia , Humanos , Rim/irrigação sanguínea , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS: The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), ß2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS: Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS: Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.
Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatias Diabéticas/diagnóstico , Hemodinâmica/fisiologia , Rim/irrigação sanguínea , Rim/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Canadá , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Lipocalina-2/análise , Lipocalina-2/sangue , Longevidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fluxo Sanguíneo Regional/fisiologia , Resistência Vascular/fisiologia , Microglobulina beta-2/análise , Microglobulina beta-2/sangueRESUMO
Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m2 and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/epidemiologia , Frequência Cardíaca/fisiologia , Fatores Etários , Idoso , Canadá/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Humanos , Longevidade/fisiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS). METHODS: We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels. RESULTS: In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p = 4.13 × 10-8), meeting the genome-wide significance threshold (p < 5 × 10-8). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07-0.10, p = 8.43 × 10-8). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (ß [SE] = - 0.39 [0.07], p = 9.72 × 10-8). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p = 3.49 × 10-8). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes. CONCLUSIONS/INTERPRETATION: We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.
Assuntos
Peptídeo C/sangue , Cromossomos Humanos Par 1/genética , Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade Classe I/genética , Adolescente , Adulto , Alelos , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M). METHODS: CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. RESULTS: Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = -0.424, p = 0.02), large (r = -0.413, p = 0.02) and intermediate (r = -0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05). CONCLUSIONS: Low OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation.
Assuntos
Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 1/sangue , Lipoproteínas HDL/administração & dosagem , Lipoproteínas HDL/sangue , Monócitos/metabolismo , Osteocalcina/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Osteocalcina/antagonistas & inibidores , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo , Células U937RESUMO
BACKGROUND: Older patients with longstanding type 1 diabetes have high cardiovascular disease (CVD) risk such that statin therapy is recommended independent of prior CVD events. We aimed to determine self-reported CVD prevention guideline adherence in patients with longstanding diabetes. RESEARCH DESIGN AND METHODS: 309 Canadians with over 50 years of type 1 diabetes completed a medical questionnaire for presence of lifestyle and pharmacological interventions, stratified into primary or secondary CVD prevention subgroups based on absence or presence of self-reported CVD events, respectively. Associations with statin use were analyzed using multivariable logistic regression. RESULTS: The 309 participants had mean ± SD age 65.7 ± 8.5 years, median diabetes duration 54.0 [IQR 51.0, 59.0] years, and HbA1c of 7.5 ± 1.1 % (58 mmol/mol). 159 (52.7 %) participants reported diet adherence, 296 (95.8 %) smoking avoidance, 217 (70.5 %) physical activity, 218 (71.5 %) renin-angiotensin-system inhibitor use, and 220 (72.1 %) statin use. Physical activity was reported as less common in the secondary prevention subgroup, and current statin use was significantly lower in the primary prevention subgroup (65.5 % vs. 84.8 %, p = 0.0004). In multivariable logistic regression, the odds of statin use was 0.38 [95 % CI 0.15-0.95] in members of the primary compared to the secondary prevention subgroup, adjusting for age, sex, hypertension history, body mass, HbA1c, cholesterol, microvascular complications, acetylsalicylic acid use, and renin-angiotensin system inhibitor use. CONCLUSION: Despite good self-reported adherence to general CVD prevention guidelines, against the principles of these guidelines we found that statin use was substantially lower in those without CVD history. Interventions are needed to improve statin use in older type 1 diabetes patients without a history of CVD.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 1/terapia , Dislipidemias/tratamento farmacológico , Fidelidade a Diretrizes , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Longevidade , Adesão à Medicação , Prevenção Primária/métodos , Comportamento de Redução do Risco , Prevenção Secundária/métodos , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Canadá , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Distribuição de Qui-Quadrado , Estudos Transversais , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Dieta/efeitos adversos , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Exercício Físico , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Atividade Motora , Análise Multivariada , Razão de Chances , Guias de Prática Clínica como Assunto , Fatores de Risco , Autorrelato , Fumar/efeitos adversos , Abandono do Hábito de Fumar , Prevenção do Hábito de Fumar , Fatores de Tempo , Resultado do TratamentoRESUMO
Patients with type 1 diabetes (T1DM) experience a disproportionate number of fractures for their bone mineral density (BMD). Differences in bone microarchitecture from those without the disease are thought to be responsible. However, the literature is inconclusive. New studies of the microarchitecture using three-dimensional imaging have the advantage of providing in vivo estimates of "bone quality," rather than examining areal BMD alone. There are drawbacks in that most studies have been done on those with less than a 30-year duration of T1DM, and the techniques used to measure vary as do the sites assessed. In addition to the rise in these imaging techniques, very recent literature presents evidence of an intimate relationship between skeletal health and vascular complications in T1DM. The following review provides an overview of the available studies of the bone microarchitecture in T1DM with a discussion of the burgeoning field of complications and skeletal health.
Assuntos
Doenças Ósseas/epidemiologia , Osso e Ossos/diagnóstico por imagem , Osso Esponjoso/diagnóstico por imagem , Osso Cortical/diagnóstico por imagem , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Fraturas Ósseas/epidemiologia , Absorciometria de Fóton , Doenças Ósseas/diagnóstico por imagem , Complicações do Diabetes/diagnóstico por imagem , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios XAssuntos
Córnea/inervação , Diabetes Mellitus Tipo 1/patologia , Neuropatias Diabéticas/patologia , Longevidade/fisiologia , Fibras Nervosas/patologia , Idoso , Canadá , Diabetes Mellitus Tipo 1/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Feminino , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-IdadeRESUMO
AIM: Physical activity (PA) is recommended to improve glycemic control in T1D; however, the effect of PA on distal symmetric polyneuropathy (DSPN) and cardiac autonomic function in longstanding T1D is unknown. METHODS: Data from 75 participants were collected as part of the Canadian Study of Longevity in T1D. Participants completed a physical exam, medical history, extensive complications phenotyping and reported their daily PA from the preceding 12-months. Pearson and Spearman correlations were used to assess PA time and complications variables. Linear regression was used to test associations between PA time, neurological and electrophysiological measures. Univariable regression was used to indicate the change in the given independent variables associated with a 30-min increase in PA per week. RESULTS: Participants were 66 ± 8 years old with diabetes duration of 54 [52,58] years, HbA1c was 7.3 ± 0.8, 65(89%) had DSPN. Weekly PA time was 156 ± 132 min, and 35(47%) reported â§150 min/week. Participants with DSPN reported lower PA time compared to individuals without DSPN (141 ± 124 min/week vs. 258 ± 129 min/week; p = 0.015). PA time was associated with better cooling detection threshold (r = 0.24; p = 0.043), peroneal and sural amplitude (r = 0.36; p = 0.0017, rs = 0.26; p = 0.024) and conduction velocity (rs = 0.28; p = 0.015, r = 0.23; p = 0.050). Linear regression adjusting for age and HbA1c, showed that for each 30-min of PA there was a 0.09mv higher peroneal amplitude (p = 0.032) and 0.048 ms lower peroneal F-wave latency (p = 0.022). CONCLUSION: In longstanding T1D, PA time is associated with superior large nerve fibre function in the lower limbs and some better measures of small nerve fibre function.
Assuntos
Diabetes Mellitus Tipo 1 , Neuropatias Diabéticas , Idoso , Canadá/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Exercício Físico , Humanos , Longevidade , Pessoa de Meia-IdadeRESUMO
AIMS: To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls. METHODS: Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RA) and efferent (RE) arteriolar resistances were estimated using the Gomez equations in 74 participants with T1D and in 75 controls. Diabetic kidney disease (DKD) non-resistors were defined by eGFRMDRD < 60 ml/min/1.73 m2 or 24-h urine albumin excretion >30 mg/day. Linear regression was applied to examine the relationships between renal function (dependent variable) and neuropathy measures (independent variable), adjusted for age, sex, HbA1c, systolic blood pressure, low density lipoprotein cholesterol, and 24-h urine albumin to creatinine ratio. RESULTS: Higher mTCNS associated with lower renal blood flow (ß ± SE:-9.29 ± 4.20, p = 0.03) and greater RE (ß ± SE:32.97 ± 15.43, p = 0.04) in participants with T1D, but not in controls. DKD non-resistors had a higher mTCNS and worse measures of corneal nerve morphology compared to those without DKD. Renal hemodynamic parameters did not associate with autonomic nerve function. CONCLUSIONS: Although neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.
Assuntos
Diabetes Mellitus Tipo 1 , Nefropatias Diabéticas , Adulto , Humanos , Longevidade/fisiologia , Canadá/epidemiologia , Hemodinâmica/fisiologia , Taxa de Filtração Glomerular , AlbuminasRESUMO
OBJECTIVES: To examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 November 2020. DESIGN: Observational cohort study. SETTING: COVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA. PARTICIPANTS: There were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident acute clinical outcomes, including in-hospital all-cause mortality. RESULTS: Respectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50- 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by -0.036 per month (95% CI -0.042 to -0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI -0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were -0.024 (95% CI -0.032 to -0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort. CONCLUSION: The incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes.
Assuntos
COVID-19 , Adulto , COVID-19/epidemiologia , Estudos de Coortes , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , SARS-CoV-2RESUMO
OBJECTIVE: Early diagnosis and treatment initiation are important factors for successful treatment of mucopolysaccharidosis type I (MPS I). The purpose of this observational study was to assess whether age at diagnosis and time to first treatment for individuals with MPS I have improved over the last 15 years. STUDY DESIGN: Data from the MPS I Registry (NCT00144794) for individuals with attenuated or severe disease who initiated therapy with laronidase enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT) between 1 January 2003 and 31 December 2017 were included. RESULTS: Data were available for 740 individuals with attenuated (n=291) or severe (n=424) MPS I (unknown n=25). Median age at diagnosis for attenuated disease did not change over time and ranged between 4.5 and 6 years of age while the median duration from diagnosis to first ERT decreased from 5.6 years before/during 2004 to 2.4 months in 2014-2017. For severe MPS I treated with HSCT, median age at diagnosis was less than 1 year and median time to first treatment was less than 3 months throughout the 15-year observation period. CONCLUSIONS: Times to diagnosis and HSCT initiation for individuals with severe MPS I were consistent over time. For individuals with attenuated MPS I, the time to ERT initiation after diagnosis has improved substantially in the last 15 years, but median age at diagnosis has not improved. Efforts to improve early diagnosis in attenuated MPS I are needed to ensure that patients receive appropriate treatment at the optimal time.
Assuntos
Diagnóstico Tardio/estatística & dados numéricos , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/terapia , Tempo para o Tratamento/estatística & dados numéricos , Criança , Pré-Escolar , Progressão da Doença , Terapia de Reposição de Enzimas/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Mucopolissacaridose I/genética , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To examine age, gender, and temporal differences in baseline characteristics and clinical outcomes of adult patients hospitalised with COVID-19. DESIGN: A cohort study using deidentified electronic medical records from a Global Research Network. SETTING/PARTICIPANTS: 67 456 adult patients hospitalised with COVID-19 from the USA; 7306 from Europe, Latin America and Asia-Pacific between February 2020 and January 2021. RESULTS: In the US cohort, compared with patients 18-34 years old, patients ≥65 had a greater risk of intensive care unit (ICU) admission (adjusted HR (aHR) 1.73, 95% CI 1.58 to 1.90), acute respiratory distress syndrome(ARDS)/respiratory failure (aHR 1.86, 95% CI 1.76 to 1.96), invasive mechanical ventilation (IMV, aHR 1.93, 95% CI, 1.73 to 2.15), and all-cause mortality (aHR 5.6, 95% CI 4.36 to 7.18). Men appeared to be at a greater risk for ICU admission (aHR 1.34, 95% CI 1.29 to 1.39), ARDS/respiratory failure (aHR 1.24, 95% CI1.21 to 1.27), IMV (aHR 1.38, 95% CI 1.32 to 1.45), and all-cause mortality (aHR 1.16, 95% CI 1.08 to 1.24) compared with women. Moreover, we observed a greater risk of adverse outcomes during the early pandemic (ie, February-April 2020) compared with later periods. In the ex-US cohort, the age and gender trends were similar; for the temporal trend, the highest proportion of patients with all-cause mortality were also in February-April 2020; however, the highest percentages of patients with IMV and ARDS/respiratory failure were in August-October 2020 followed by February-April 2020. CONCLUSIONS: This study provided valuable information on the temporal trends of characteristics and outcomes of hospitalised adult COVID-19 patients in both USA and ex-USA. It also described the population at a potentially greater risk for worse clinical outcomes by identifying the age and gender differences. Together, the information could inform the prevention and treatment strategies of COVID-19. Furthermore, it can be used to raise public awareness of COVID-19's impact on vulnerable populations.
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COVID-19 , Adolescente , Adulto , Estudos de Coortes , Feminino , Saúde Global , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pandemias , Respiração Artificial , SARS-CoV-2 , Adulto JovemRESUMO
OBJECTIVE: A subset of people with long-standing type 1 diabetes (T1D) appears to be protected from microvascular and macrovascular complications. Previous studies have focused on improved abilities to respond to glucose and its downstream effects as protective mechanisms. It is unclear whether lipoproteins play a role in the vascular health of these people. We therefore determined whether HDL particle concentration, size, function, and/or protein composition associate with protection from vascular complications. RESEARCH DESIGN AND METHODS: We studied two independent cross-sectional cohorts with T1D: the T1D Exchange Living Biobank (n = 47) and the Joslin Medalist Study (n = 100). Some of the subjects had vascular complications, whereas others never exhibited vascular complications, despite an average duration of diabetes in the cohorts of 45 years. We assessed HDL particle size and concentration by calibrated ion mobility analysis, the HDL proteome by targeted mass spectrometry, and HDL function ex vivo by quantifying cholesterol efflux capacity and inhibition of monocyte adhesion to endothelial cells. RESULTS: In both cohorts, people without vascular complications exhibited significantly higher concentrations of medium-sized HDL particles (M-HDL) independently of total and HDL cholesterol levels. While no consistent differences in HDL functions were observed ex vivo, people without vascular complications had higher levels of HDL-associated paraoxonase 1 (PON1), an enzyme that inhibits atherosclerosis in animal models. CONCLUSIONS: Elevated concentrations of M-HDL particles and elevated levels of HDL-associated PON1 may contribute to long-term protection from the vascular complications of diabetes by pathways that are independent of total cholesterol and HDL cholesterol.
Assuntos
Arildialquilfosfatase/sangue , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 1/sangue , Angiopatias Diabéticas/prevenção & controle , Adulto , Idoso , Aterosclerose/sangue , Aterosclerose/etiologia , HDL-Colesterol/metabolismo , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Angiopatias Diabéticas/sangue , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
AIM: It is currently unclear if longstanding type 1 diabetes (T1D) affects bone mineral density (BMD). METHODS: BMD measured by dual-energy X-ray absorptiometry and history of fragility fracture was determined in 75 T1D participants with ≥50â¯years of diabetes duration and 75 age- and sex-matched non-diabetic controls. BMD T-scores were determined for the lumbar spine (LS), total hip (TH) and femoral neck (FN). RESULTS: T1D participants had median diabetes duration of 54 [52, 58] years, 41 (55%) were females, and mean A1c was 7.3⯱â¯0.8%. T1D females had higher LS T-scores compared to female controls (-0.3⯱â¯1.2 vs. -1.1⯱â¯1.4, pâ¯=â¯0.014), lower FN T-scores (-1.5⯱â¯1.0 vs. -1.2⯱â¯0.9, pâ¯=â¯0.042) and more fragility fractures (7 (17%) vs. 1 (2%), pâ¯=â¯0.021). In T1D, higher A1c was associated with higher adjusted odds of fragility fracture (pâ¯=â¯0.006). T1D males and controls showed no difference in BMD or fractures. CONCLUSIONS: There were no substantial differences in T-score between T1D and matched controls; however, T1D females showed higher BMD at the LS and possibly paradoxically higher fragility fractures compared to matched controls. These findings suggest that lower T-scores may not be associated with a history of fragility fracture in females with longstanding T1D and that other factors should be investigated.
Assuntos
Densidade Óssea , Diabetes Mellitus Tipo 1/fisiopatologia , Longevidade , Absorciometria de Fóton , Idoso , Canadá , Diabetes Mellitus Tipo 1/complicações , Feminino , Colo do Fêmur , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/fisiopatologia , Humanos , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Fatores SexuaisRESUMO
Cyclic guanosine monophosphate (cGMP) influences intrarenal hemodynamics in animal models, but the relationship between cGMP and renal function in adults with type 1 diabetes (T1D) remains unclear. In this study, plasma cGMP correlated with efferent arteriolar resistance, effective renal plasma flow, and renal vascular resistance in adults with T1D.
Assuntos
Arteríolas/fisiopatologia , GMP Cíclico/sangue , Diabetes Mellitus Tipo 1/sangue , Rim/irrigação sanguínea , Idoso , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Hemodinâmica , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Circulação Renal/fisiologia , Resistência VascularRESUMO
BACKGROUND: Periodontitis is more common and severe in people with diabetes than the general population. We have reported in the Joslin Medalist Study that people with type 1 diabetes of ≥50 years (Medalists) may have endogenous protective factors against diabetic nephropathy and retinopathy. METHODS: In this cross-sectional study, the prevalence of periodontitis according to the Centers for Disease Control/American Academy of Periodontology classification in a subset (n = 170, mean age = 64.6 ± 6.9 years) of the Medalist cohort, and its associations to various criteria of periodontitis and diabetic complications were assessed. RESULTS: The prevalence of severe periodontitis in Medalists was only 13.5% which was lower than reported levels in diabetic patients of similar ages. Periodontal parameters, including bleeding on probing, plaque index, gingival index, and demographic traits, including male sex, chronological age, and age at diagnosis were significantly associated with severity of periodontitis, which did not associate with diabetes duration, hemoglobin A1c (HbA1c), body mass index, and lipid profiles. Random serum C-peptide levels inversely associated with severity of periodontitis (P = 0.03), lower probing depth (P = 0.0002), and clinical attachment loss (P = 0.03). Prevalence of cardiovascular diseases (CVD) and systemic inflammatory markers, plasma interleukin-6 (IL-6), and serum immunoglobulin G titer against Porphyromonas gingivalis positively associated with severity of periodontitis (P = 0.002 and 0.02, respectively). Antibody titer to P. gingivalis correlated positively and significantly with CVD, serum IL-6, and high-sensitivity C-reactive protein. CONCLUSIONS: Some Medalists could be protected from severe periodontitis even with hyperglycemia. Endogenous protective factors for periodontitis could possibly be related to residual insulin production and lower levels of chronic inflammation.