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2.
J Am Soc Nephrol ; 30(10): 2000-2016, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31537649

RESUMO

BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

4.
J Clin Invest ; 130: 4165-4179, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31295146

RESUMO

Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency rather than hyperglycemia elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we investigated the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic Apoc3 expression in diabetic mice - resulting in lower levels of TRLs - without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and the accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibiting APOC3 might reduce CVD risk in T1DM patients.

5.
Arterioscler Thromb Vasc Biol ; 39(7): 1483-1491, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31092010

RESUMO

Objective- Albuminuria is an important risk factor for cardiovascular disease in diabetes mellitus. We determined whether albuminuria associates with alterations in the proteome of HDL (high-density lipoprotein) of subjects with type 1 diabetes mellitus and whether those alterations associated with coronary artery calcification. Approach and Results- In a cross-sectional study of 191 subjects enrolled in the DCCT (Diabetes Control and Complications Trial)/EDIC study (Epidemiology of Diabetes Interventions and Complications), we used isotope dilution tandem mass spectrometry to quantify 46 proteins in HDL. Stringent statistical analysis demonstrated that 8 proteins associated with albuminuria. Two of those proteins, AMBP (α1-microglobulin/bikunin precursor) and PTGDS (prostaglandin-H2 D-isomerase), strongly and positively associated with the albumin excretion rate ( P<10-6). Furthermore, PON (paraoxonase) 1 and PON3 levels in HDL strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (95% CI, 0.43-0.92; P=0.018) for PON1 and 0.59 (95% CI, 0.40-0.87; P=0.0079) for PON3. Only 1 protein, PON1, associated with both albumin excretion rate and coronary artery calcification. Conclusions- Our observations indicate that the HDL proteome is remodeled in type 1 diabetes mellitus subjects with albuminuria. Moreover, low concentrations of the antiatherosclerotic protein PON1 in HDL associated with both albuminuria and coronary artery calcification, raising the possibility that alterations in HDL protein cargo mediate, in part, the known association of albuminuria with cardiovascular risk in type 1 diabetes mellitus. Visual Overview- An online visual overview is available for this article.

6.
Nutr J ; 18(1): 23, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943964

RESUMO

BACKGROUND: Dietary fiber has been recommended for glucose control, and typically low intakes are observed in the general population. The role of fiber in glycemic control in reported literature is inconsistent and few reports are available in populations with type 1 diabetes (T1D). METHODS: Using data from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study [n = 1257; T1D: n = 568; non-diabetic controls: n = 689] collected between March 2000 and April 2002, we examined cross-sectional (baseline) and longitudinal (six-year follow-up in 2006-2008) associations of dietary fiber and HbA1c. Participants completed a validated food frequency questionnaire, and a physical examination and fasting biochemical analyses (12 h fast) at baseline visit and at the year 6 visit. We used a linear regression model stratified by diabetes status, and adjusted for age, sex and total calories, and diabetes duration in the T1D group. We also examined correlations of dietary fiber with HbA1c. RESULTS: Baseline dietary fiber intake and serum HbA1c in the T1D group were 16 g [median (IQ): 11-22 g) and 7.9 ± 1.3% mean (SD), respectively, and in the non-diabetic controls were 15 g [median (IQ): 11-21 g) and 5.4 ± 0.4%, respectively. Pearson partial correlation coefficients revealed a significant but weak inverse association of total dietary fiber with HbA1c when adjusted for age, sex, diabetes status and total calories (r = - 0.07, p = 0.01). In the adjusted linear regression model at baseline, total dietary fiber revealed a significant inverse association with HbA1c in the T1D group [ß ± SE = - 0.32 ± 0.15, p = 0.034], as well as in the non-diabetic controls [- 0.10 ± 0.04, p = 0.009]. However, these results were attenuated after adjustment for dietary carbohydrates, fats and proteins, or for cholesterol and triglycerides. No such significance was observed at the year 6 follow-up, and with the HbA1c changes over 6 years. CONCLUSION: Thus, at observed levels of intake, total dietary fiber reveals modest inverse associations with poor glycemic control. Future studies must further investigate the role of overall dietary quality adjusting for fiber-rich foods in T1D management.

7.
Pediatr Diabetes ; 20(5): 594-603, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31017351

RESUMO

OBJECTIVES: To determine trajectories of glycemic control and body mass index (BMI) z-score in a large pediatric sample with type 1 diabetes (T1D) over a 38-year period, and to evaluate sex differences and temporal changes in the prevalence of these trajectories. METHODS: We conducted a longitudinal, retrospective study of 7002 2 to 18 year olds with T1D followed between 1978 and 2016 at a single center. Group-based modeling was used to identify trajectories for hemoglobin A1c (HbA1c) and BMI z-score. Multinomial logistic regression identified predictors of membership to less favorable glycemic trajectories. RESULTS: Group-based modeling yielded 5 HbA1c trajectories. A total of 86% of the sample fell within 3 trajectories that were largely stable across childhood and adolescence, and 14% fell within 2 trajectories characterized by marked deterioration beginning in pre-adolescence. Girls were more likely to be in the HbA1c trajectory with the highest starting HbA1c and significant deterioration during adolescence, and in the highest two BMI z-score trajectories. Patients with non-white race had the highest odds of belonging to a less favorable HbA1c trajectory. Prevalence of the high stable HbA1c trajectory decreased and prevalence of the low stable HbA1c trajectory increased over the study period. CONCLUSIONS: A minority of youth with T1D experienced deterioration of glycemic control during adolescence. Girls were more likely to belong to the worst HbA1c trajectory and to BMI z-score trajectories in the overweight/obese range, which may increase cardiometabolic risk. Addressing racial/ethnic disparities in glycemic control should remain a priority. Advances in T1D management correlated with favorable shifts in HbA1c trajectory prevalence.

8.
Bone ; 123: 260-264, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30936041

RESUMO

Women with type 1 diabetes (T1D) are at increased risk for fracture. We studied the association of T1D and young age at T1D onset (T1D onset before 20 years) on bone structural quality. 24 postmenopausal women with T1D (mean age 60.9 years, mean T1D duration 41.7 years) and 22 age, sex- and body mass index (BMI)-matched controls underwent dual X-ray absorptiometry (DXA) measured areal bone mineral density (aBMD) at the lumbar spine, hip and distal radius. Bone mass, geometry and estimated bone strength were assessed at distal and shaft of non-dominant radius and tibia using peripheral quantitative computed tomography (pQCT). Postmenopausal women with T1D had lower trabecular volumetric bone mineral density (vBMD) (LSM ±â€¯SEM; 166.1 ±â€¯8.2 vs 195.9 ±â€¯8.3 mg/cm3, p = 0.02) and compressive bone strength (24.6 ±â€¯1.8 vs 30.1 ±â€¯1.9 mg2/mm4, p = 0.04) at the distal radius compared to controls adjusting for age, BMI and radius length. At the distal radius, patients with young onset T1D had lower total vBMD (258.7 ±â€¯19.7 vs 350.8 ±â€¯26.1 mg/cm3, p = 0.02) and trabecular vBMD (141.4 ±â€¯11.6 vs 213.6 ±â€¯15.4 mg/cm3, p = 0.003) compared to adult onset T1D patients adjusting for age, BMI and the radius length. At the tibial shaft, young onset T1D patients had larger endosteal circumference (39.1 ±â€¯1.2 vs 32.1 ±â€¯1.6 mm, p = 0.005) with similar periosteal circumference (67.1 ±â€¯0.9 vs 65.1 ±â€¯1.2 mm, p = 0.2) resulting in reduced cortical thickness (4.4 ±â€¯0.1 vs 5.2 ±â€¯0.1 mm, p = 0.004) compared to adult onset T1D patients adjusting for age, BMI and the tibia length. There was no difference in the lumbar spine, femoral neck, total hip and distal radius DXA-measured aBMD between subjects with T1D and controls. T1D is associated with lower trabecular vBMD at the distal radius. T1D onset before age 20 is associated with cortical bone size deficits at the tibial shaft.

9.
Curr Biol ; 29(6): 957-967.e4, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30827911

RESUMO

People commonly increase sleep duration on the weekend to recover from sleep loss incurred during the workweek. Whether ad libitum weekend recovery sleep prevents metabolic dysregulation caused by recurrent insufficient sleep is unknown. Here, we assessed sleep, circadian timing, energy intake, weight gain, and insulin sensitivity during sustained insufficient sleep (9 nights) and during recurrent insufficient sleep following ad libitum weekend recovery sleep. Healthy, young adults were randomly assigned to one of three groups: (1) control (CON; 9-h sleep opportunities, n = 8), (2) sleep restriction without weekend recovery sleep (SR; 5-h sleep opportunities, n = 14), and (3) sleep restriction with weekend recovery sleep (WR; insufficient sleep for 5-day workweek, then 2 days of weekend recovery, then 2 nights of insufficient sleep, n = 14). For SR and WR groups, insufficient sleep increased after-dinner energy intake and body weight versus baseline. During ad libitum weekend recovery sleep, participants cumulatively slept ∼1.1 h more than baseline, and after-dinner energy intake decreased versus insufficient sleep. However, during recurrent insufficient sleep following the weekend, the circadian phase was delayed, and after-dinner energy intake and body weight increased versus baseline. In SR, whole-body insulin sensitivity decreased ∼13% during insufficient sleep versus baseline, and in WR, whole-body, hepatic, and muscle insulin sensitivity decreased ∼9%-27% during recurrent insufficient sleep versus baseline. Furthermore, during the weekend, total sleep duration was lower in women versus men, and energy intake decreased to baseline levels in women but not in men. Our findings suggest that weekend recovery sleep is not an effective strategy to prevent metabolic dysregulation associated with recurrent insufficient sleep.

10.
Diabetes ; 68(4): 858-867, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30674623

RESUMO

Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 × 10-8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 × 10-8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ≤ 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.


Assuntos
Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla/métodos , Hemoglobina A Glicada/genética , Glicemia/metabolismo , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino
11.
Can J Diabetes ; 43(1): 34-39, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30026043

RESUMO

OBJECTIVES: Copeptin, a surrogate marker for vasopressin, is elevated in participants with insulin resistance (IR) and type 2 diabetes. Whereas adults with type 1 diabetes also demonstrate elevated copeptin concentrations and IR compared to controls without diabetes, the relationship between copeptin and IR in type 1 diabetes is unclear. METHODS: Participants with (n=209) and without (n=244) type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, vitals, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, glycated hemoglobin and lipid panels. Estimated insulin sensitivity (eIS) was calculated by validated equations in participants with and without type 1 diabetes. The relationships among copeptin, IR, waist circumference (WC) and body mass index (BMI) were examined with unadjusted and adjusted linear regression models. RESULTS: Copeptin was correlated with eIS (R=-0.17, R2=0.029), WC (R=0.16, R2=0.026) and BMI (R=0.22, R2=0.048) for type 1 diabetes and with eIS (R=-0.37, R2=0.14), WC (R=0.40, R2=0.16) and BMI (R=0.25, R2=0.063) in non-type 1 diabetes. In multivariable analysis, copeptin correlated with total cholesterol (beta±SE: -0.12±0.04, p=0.008) and low-density lipoprotein (beta±SE: -0.11±0.04, p=0.01) in type 1 diabetes. In non-type 1 diabetes, copeptin was associated with WC (beta±SE: 0.14±0.04, p=0.0024), BMI (beta±SE: 0.13±0.04, p=0.007) and eIS (beta±SE: -0.14±0.04, p=0.0013). CONCLUSIONS: Copeptin does not correlate with markers of IR in type 1 diabetes but strongly correlates in non-type 1 diabetes. Thus, elevated vasopressin activity and IR appear to be independent risk factors for vascular complications in type 1 diabetes.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Glicopeptídeos/sangue , Resistência à Insulina/fisiologia , Adulto , Biomarcadores/sangue , Doença da Artéria Coronariana/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Diabetes Obes Metab ; 21(3): 575-583, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30311395

RESUMO

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.

13.
Diabetes Care ; 42(2): 297-302, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30482755

RESUMO

OBJECTIVE: Novel biomarkers are needed to better predict coronary artery calcification (CAC), a marker of subclinical atherosclerosis, and diabetic kidney disease (DKD) in type 1 diabetes. We evaluated the associations between serum uromodulin (SUMOD [a biomarker associated with anti-inflammatory and renal protective properties]), CAC progression, and DKD development over 12 years. RESEARCH DESIGN AND METHODS: Participants (n = 527, 53% females) in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were examined during 2002-2004, at a mean age of 39.6 ± 9.0 years and a median duration of diabetes of 24.8 years. Urine albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) determined by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation were measured at baseline and after a mean follow-up period of 12.1 ± 1.5 years. Elevated albumin excretion was defined as ACR ≥30 mg/g, rapid GFR decline (>3 mL/min/1.73 m2/year), and impaired GFR as eGFR <60 mL/min/1.73 m2. SUMOD was measured on stored baseline plasma samples (Meso Scale Discovery). CAC was measured using electron beam computed tomography. CAC progression was defined as a change in the square root-transformed CAC volume of ≥2.5. RESULTS: Higher baseline SUMOD level conferred lower odds of CAC progression (odds ratio 0.68; 95% CI 0.48-0.97), incident elevated albumin excretion (0.37; 0.16-0.86), rapid GFR decline (0.56; 0.35-0.91), and impaired GFR (0.44; 0.24-0.83) per 1 SD increase in SUMOD (68.44 ng/mL) after adjustment for baseline age, sex, systolic blood pressure, LDL cholesterol, and albuminuria/GFR. The addition of SUMOD to models with traditional risk factors also significantly improved the prediction performance for CAC progression and incident DKD. CONCLUSIONS: Higher baseline SUMOD level predicted lower odds of both CAC progression and incident DKD over 12 years in adults with type 1 diabetes.


Assuntos
Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatias Diabéticas/diagnóstico , Uromodulina/sangue , Calcificação Vascular/diagnóstico , Adulto , Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Calcificação Vascular/complicações , Calcificação Vascular/epidemiologia , Adulto Jovem
14.
Diabetes Technol Ther ; 21(1): 6-10, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575413

RESUMO

BACKGROUND: We investigated the efficacy and safety of continuous glucose monitoring (CGM) initiation within 1 year of type 1 diabetes (T1D) diagnosis among children, adolescents, and adults. METHODS: Differences in mean A1c (primary outcome) and diabetes-related emergency visits (secondary outcome) for 2.5 years between early CGM users and non-CGM users were studied among 396 newly diagnosed patients with T1D (94% children [age <18 years], 5% adults, 46% females) between January 2013 and December 2015 at Barbara Davis Center for Diabetes. The primary outcome was adjusted by age at diagnosis and gender. P < 0.05 was considered significant. RESULTS: Gender, ethnicity, body mass index, and A1c at diagnosis were similar between the groups. Irrespective of insulin delivery methods, CGM users had a significantly greater improvement in glycemic control than non-CGM users at 1, 1.5, 2, and 2.5 years. For 2.5 years of follow-up, the multiple daily injection (MDI)+CGM group (n = 19) had 1.5% ± 0.2% lower A1c than the MDI only group (n = 225) (7.7% ± 0.2% vs. 9.2% ± 0.04%, P < 0.0001), and the insulin pump (continuous subcutaneous insulin infusion [CSII])+CGM group (n = 62) had 0.7% ± 0.1% lower A1c than the CSII only group (n = 90) (8.0% ± 0.08% vs. 8.7% ± 0.07%, P < 0.0001). The MDI+CGM group had significantly lower A1c than the CSII only group (7.7% ± 0.2% vs. 8.7% ± 0.07%, P < 0.0001). The number of diabetes-related (severe hypoglycemia or hyperglycemia) emergency department visits was significantly lower among early CGM users compared with non-CGM users (P = 0.003). CONCLUSION: Irrespective of insulin delivery system, early initiation of CGM within 1 year from T1D diagnosis was associated with better glucose control and fewer diabetes-related emergency visits.


Assuntos
Fatores Etários , Automonitorização da Glicemia/métodos , Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Autogestão/estatística & dados numéricos , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/terapia , Feminino , Hemoglobina A Glicada/análise , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/epidemiologia , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Resultado do Tratamento , Adulto Jovem
15.
Diabetes Technol Ther ; 20(10): 639-647, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30207748

RESUMO

BACKGROUND: The majority of therapies have generally targeted fasting glucose control, and current mealtime insulin therapies have longer time action profiles than that of endogenously secreted insulin. The primary purpose of this study was to assess both glucose time-in-range (TIR: 70-180 mg/dL) and postprandial glucose excursions (PPGE) in 1-4 h using a real-time continuous glucose monitor (CGM) with Technosphere insulin (TI) versus insulin aspart in patients with type 1 diabetes (T1DM) on multiple daily injections (MDI). RESEARCH DESIGN AND METHODS: This pilot, investigator-led, collaborative, open-label, multicenter, clinical research trial enrolled 60 patients with T1DM with HbA1c levels ≥6.5% and ≤10%. Individuals were randomized to treatment with titrated TI (n = 26) or titrated insulin aspart (n = 34), stratified by baseline HbA1c levels (≤8% or >8%). All were required to wear a real-time CGM throughout the trial. All patients in the TI group were advised to take supplemental inhalations at 1 and 2 h after meals if indicated based on postprandial glucose (PPG) values. The coprimary outcomes were assessed both in the full intent-to-treat population and in those individuals randomized to TI who were compliant with supplemental doses ≥90% of the time (n = 15). The CGM data were analyzed using linear regression models. RESULTS: Overall, those treated with TI versus aspart achieved comparable TIR, but less time spent in hypoglycemia (<60 and <50 mg/dL, both P < 0.05). In the TI-compliant group (n = 15), TIR was significantly greater (62.5% ± 2.6% vs. 53.8% ± 1.7%, P = 0.009) and time in hyperglycemia >180 mg/dL was lower (34.2% ± 2.7% vs. 41.0% ± 1.7%, P = 0.045) as compared with the aspart group. PPG was also significantly lower in the TI cohort at 60 and 90 min postmeal, and PPGE were lower in the TI-compliant group as compared with the aspart group over 1-4-h postmeal (P < 0.05). In addition, there was weight gain in the aspart group compared with weight loss in the TI group (P = 0.006) despite higher prandial TI insulin dose. CONCLUSIONS: We conclude that using TI appropriately at mealtimes with supplemental dosing improves prandial glucose (TIR and 1-4 h) control without any increase in time in hypoglycemia or weight gain in patients with T1DM on MDI. The study results support a larger study using a treat-to-target design to confirm these findings. Clinical trial reg. no. NCT03143816, clinicaltrials.gov .


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Administração por Inalação , Adulto , Automonitorização da Glicemia , Sistemas de Liberação de Medicamentos , Feminino , Hemoglobina A Glicada/análise , Humanos , Hiperglicemia/sangue , Injeções , Insulina Aspart/administração & dosagem , Insulina Aspart/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento , Ganho de Peso
16.
J Diabetes Complications ; 32(10): 961-965, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30121205

RESUMO

AIMS: To evaluate gender differences in diabetes self-care components including glycemic, blood pressure and lipid control, utilization of diabetes technologies and acute diabetes complications in adults with type 1 diabetes. METHODS: A total of 9,481 participants >18 years were included in the analysis, 53% were female. Variables of interest included glycemic control measured by HbA1c, systolic/diastolic blood pressures, presence of dyslipidemia, insulin delivery modality, and rates of acute complications. RESULTS: Glycemic control was similar in women and men (mean HbA1c in both groups: 8.1% ±â€¯1.6% (64 ±â€¯16 mmol/mol), (p = 0.54). More women used insulin pump therapy (66% vs. 59%, p < 0.001) but use of sensor technology was similar (p < = 0.42). Women had higher rates of diabetic ketoacidosis (DKA) (5% vs. 3%, p < 0.001) and eating disorders (1.7% vs. 0.1%, p < 0.001). Severe hypoglycemia rates were not different between men and women (p = 0.42). Smoking (6% vs 4%, p < 0.001), systolic (125 ±â€¯14.2 vs. 121 ±â€¯14.4, p < 0.001) and diastolic blood pressure (73.3 ±â€¯9.5 vs. 72.2 ±â€¯9.3, p < 0.001) and rate of dyslipidemia (28% vs. 23%, p < 0.001) were higher in men. CONCLUSION: While glycemic control in type 1 diabetes was similar regardless of gender, rates of DKA and eating disorders were higher in women while rates of smoking, hypertension and dyslipidemia were higher in men.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/terapia , Autocuidado/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Angiopatias Diabéticas/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Autocuidado/normas , Caracteres Sexuais , Fatores Sexuais , Adulto Jovem
17.
J Diabetes Complications ; 32(11): 975-981, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29937138

RESUMO

AIMS: Compare physical activity (PA) levels in adults with and without type 1 diabetes and identify diabetes-specific barriers to PA. METHODS: Forty-four individuals with type 1 diabetes and 77 non-diabetic controls in the Coronary Artery Calcification in Type 1 Diabetes study wore an accelerometer for 2 weeks. Moderate-to-vigorous physical activity (MVPA) was compared by diabetes status using multiple linear regression. The Barriers to Physical Activity in Type 1 Diabetes questionnaire measured diabetes-specific barriers to PA, and the Clarke hypoglycemia awareness questionnaire measured hypoglycemia frequency. RESULTS: Individuals with type 1 diabetes engaged in less MVPA, fewer bouts of MVPA, and spent less time in MVPA bouts per week than individuals without diabetes (all p < 0.05), despite no difference in self-reported PA (p > 0.05). The most common diabetes-specific barrier to PA was risk of hypoglycemia. Individuals with diabetes reporting barriers spent less time in MVPA bouts per week than those not reporting barriers (p = 0.047). CONCLUSIONS: Individuals with type 1 diabetes engage in less MVPA than those without diabetes despite similar self-reported levels, with the main barrier being perceived risk of hypoglycemia. Adults with type 1 diabetes require guidance to meet current PA guidelines and reduce cardiovascular risk.


Assuntos
Diabetes Mellitus Tipo 1/psicologia , Exercício/fisiologia , Hipoglicemia/etiologia , Hipoglicemia/psicologia , Percepção/fisiologia , Autorrelato , Acelerometria , Adulto , Idoso , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Angiopatias Diabéticas/prevenção & controle , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora , Reprodutibilidade dos Testes , Fatores de Risco , Inquéritos e Questionários
18.
Diabetes Obes Metab ; 20(7): 1776-1780, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29498467

RESUMO

Uricosuria and crystallization are increasingly recognized risk factors for diabetic tubulopathy. This pilot clinical trial aimed to determine the acute effect of urinary alkalinization using oral sodium bicarbonate (NaHCO3 ) on UA crystals in adults with type 1 diabetes (T1D). Adults with T1D, ages 18 to 65 years (n = 45, 60% female, HbA1c, 7.5 ± 1.2%, 20.2 ± 9.3 years duration) without chronic kidney disease (eGFR ≥60 mL/min/1.73 m2 and albumin-to-creatinine ratio < 30 mg/g) received 2 doses of 1950 mg oral NaHCO3 over 24 hours. Fasting urine and serum were collected pre- and post-intervention. UA crystals were identified under polarized microscopy. Urine measurements included: osmolality, pH, UA, creatinine and kidney injury molecule-1 (KIM-1). NaHCO3 therapy increased mean ± SD urine pH from 6.1 ± 0.7 to 6.5 ± 0.7 (P < .0001). Prior to therapy, 31.0% of participants had UA crystals vs 6.7% post therapy (P = .005). Change in urine pH inversely correlated with change in urine KIM-1 (r:-0.51, P = .0003). In addition, change in urine UA over 24 hours correlated with change in urine KIM-1 (r:0.37, P = .01). In conclusion, oral NaHCO3 normalized urine pH and decreased UA crystals, and may hold promise as an inexpensive and safe tubulo-protective intervention in individuals with T1D.


Assuntos
Diabetes Mellitus Tipo 1/urina , Nefropatias Diabéticas/urina , Suplementos Nutricionais , Bicarbonato de Sódio/uso terapêutico , Ácido Úrico/urina , Adulto , Creatinina/urina , Feminino , Taxa de Filtração Glomerular , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Masculino , Microscopia de Polarização , Concentração Osmolar , Projetos Piloto
19.
JCI Insight ; 3(3)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29415895

RESUMO

BACKGROUND: Accumulation of diacylglycerol (DAG) and sphingolipids is thought to promote skeletal muscle insulin resistance by altering cellular signaling specific to their location. However,the subcellular localization of bioactive lipids in human skeletal muscle is largely unknown. METHODS: We evaluated subcellular localization of skeletal muscle DAGs and sphingolipids in lean individuals (n = 15), endurance-trained athletes (n = 16), and obese men and women with (n = 12) and without type 2 diabetes (n = 15). Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/ER, and nuclear compartments. Lipids were measured using liquid chromatography tandem mass spectrometry, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp. RESULTS: Sarcolemmal 1,2-DAGs were not significantly related to insulin sensitivity. Sarcolemmal ceramides were inversely related to insulin sensitivity, with a significant relationship found for the C18:0 species. Sarcolemmal sphingomyelins were also inversely related to insulin sensitivity, with the strongest relationships found for the C18:1, C18:0, and C18:2 species. In the mitochondrial/ER and nuclear fractions, 1,2-DAGs were positively related to, while ceramides were inversely related to, insulin sensitivity. Cytosolic lipids as well as 1,3-DAG, dihydroceramides, and glucosylceramides in any compartment were not related to insulin sensitivity. All sphingolipids but only specific DAGs administered to isolated mitochondria decreased mitochondrial state 3 respiration. CONCLUSION: These data reveal previously unknown differences in subcellular localization of skeletal muscle DAGs and sphingolipids that relate to whole-body insulin sensitivity and mitochondrial function in humans. These data suggest that whole-cell concentrations of lipids obscure meaningful differences in compartmentalization and suggest that subcellular localization of lipids should be considered when developing therapeutic interventions to treat insulin resistance. FUNDING: National Institutes of Health General Clinical Research Center (RR-00036), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK089170), NIDDK (T32 DK07658), and Colorado Nutrition Obesity Research Center (P30DK048520).


Assuntos
Diglicerídeos/metabolismo , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Esfingolipídeos/metabolismo , Adulto , Biópsia , Glicemia/análise , Estudos Transversais , Citosol/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diglicerídeos/análise , Retículo Endoplasmático/metabolismo , Feminino , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Obesidade/sangue , Obesidade/metabolismo , Sarcolema/metabolismo , Esfingolipídeos/análise
20.
Diabetologia ; 61(5): 1098-1111, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29404672

RESUMO

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 Jovem
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