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1.
J Am Heart Assoc ; 10(18): e020716, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34493073

RESUMO

Background The prognostic value of anthropometric, adipokine, and computed tomography measures of adiposity to predict diabetes in Black, specifically by normoglycemia versus prediabetes, remains incompletely understood. Methods and Results Among Black participants without diabetes in the JHS (Jackson Heart Study), waist circumference [WC], body mass index, adiponectin, leptin, and leptin:adiponectin ratio were standardized in sample 1 (2422 participants at baseline [2000-2004]) and WC, body mass index, visceral adipose tissue (VAT), subcutaneous adipose tissue, and liver attenuation in 1537 participants at examination 2 (2005-2008) (sample 2). Hazard ratios (HRs) for diabetes were estimated using interval-censored Cox modeling adjusting for traditional risk factors and validated with the C index. Over 5 years, 300 and 122 incident diabetes cases occurred in sample 1 and sample 2, respectively. In sample 1 and sample 2, a 1-SD higher log-leptin:adiponectin ratio and VAT had the strongest associations (HR, 1.95 [95% CI, 1.67-2.27] and 1.76 [95% CI, 1.52-2.04]) and discriminatory power (C index 0.68 [95% CI, 0.64-0.71] and C index 0.67 [95% CI, 0.61-0.74]) with diabetes. The normoglycemic compared with the prediabetes group had a 1.3 to 1.9 times greater magnitude of associations with diabetes for WC, liver attenuation, and VAT (P interaction <0.10). In sample 2, C indices for WC (HR, 0.84; 95% CI, 0.73-0.95), VAT (HR, 0.91; 95% CI, 0.85-0.98), and liver attenuation (HR, 0.90; 95% CI, 0.77-1.00) were greater than HbA1c (HR, 0.74; 95% CI, 0.57-0.90) in normoglycemia, whereas HbA1c was best in prediabetes (HR, 0.72; 95% CI, 0.66-0.78). Conclusions Overall, among Black adults, multiple measures of adiposity were associated with incident diabetes with modest predictive ability. In Black patients with normoglycemia, WC, liver attenuation, and VAT may appropriately identify those at high risk for diabetes, whereas HbA1c was the best predictor in individuals with prediabetes.

2.
Surg Oncol ; 39: 101659, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34534729

RESUMO

BACKGROUND: Adipose tissue has emerged as an important window into cancer pathophysiology, revealing potential targets for novel therapeutic interventions. The goal of this study was to compare the breast adipose tissue (BrAT) immune milieu surrounding breast carcinoma and contralateral unaffected breast tissue obtained from the same patient. MATERIALS AND METHODS: Patients undergoing bilateral mastectomy for unilateral breast cancer were enrolled for bilateral BrAT collection at the time of operation. After BrAT was processed, adipocyte and stromal vascular fraction (SVF) gene expression was quantified by PCR. SVF cells were also processed for flow cytometric immune cell characterization. RESULTS: Twelve patients underwent bilateral mastectomy for unilateral ductal carcinoma. BrAT adipocyte CXCL2 gene expression trended higher in the tumor-affected breast as compared to the unaffected breast. Macrophage MCP-1 and PPARγ gene expression also tended to be higher in the tumor-affected breasts. T cell gene expression of FOXP3 (p = 0.0370) were significantly greater in tumor-affected breasts than unaffected breasts. Affected BrAT contained higher numbers of Th2 CD4+ cells (p = 0.0165) and eosinophils (p = 0.0095) while trending towards increased macrophage and lower Th1 CD4+ cells infiltration than tumor-affected BrAT. CONCLUSION: This preliminary study aimed to identify the immunologic environment present within BrAT and is the first to directly compare this in individual patients' tumor-associated and unaffected BrAT. These findings suggest that cancer-affected BrAT had increased levels of T cell specific FOXP3 and higher levels of anti-inflammatory/regulatory cells compared to the contralateral BrAT.

3.
Front Immunol ; 12: 650768, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248937

RESUMO

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.


Assuntos
Imunidade Adaptativa/imunologia , Adipócitos/imunologia , Tecido Adiposo/imunologia , Imunidade Inata/imunologia , Obesidade/imunologia , Adipócitos/citologia , Adipócitos/metabolismo , Adipocinas/imunologia , Adipocinas/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
4.
Hum Mol Genet ; 30(22): 2190-2204, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34165540

RESUMO

Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific.

5.
Circulation ; 143(24): 2355-2366, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33605160

RESUMO

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is an important driver of blood pressure (BP), but the association of the RAAS with ambulatory BP (ABP) and ABP monitoring phenotypes among African Americans has not been assessed. METHODS: ABP and ABP monitoring phenotypes were assessed in 912 Jackson Heart Study participants with aldosterone and plasma renin activity (PRA). Multivariable linear and logistic regression analyses were used to analyze the association of aldosterone and PRA with clinic, awake, and asleep systolic BP and diastolic BP (DBP) and ABP monitoring phenotypes, adjusting for important confounders. RESULTS: The mean age of participants was 59±11 years and 69% were female. In fully adjusted models, lower log-PRA was associated with higher clinic, awake, and asleep systolic BP and DBP (all P<0.05). A higher log-aldosterone was associated with higher clinic, awake, and asleep DBP (all P<0.05). A 1-unit higher log-PRA was associated with lower odds of daytime hypertension (odds ratio [OR] 0.59 [95% CI, 0.49-0.71]), nocturnal hypertension (OR, 0.68 [95% CI, 0.58-0.79]), daytime and nocturnal hypertension (OR, 0.59 [95% CI, 0.48-0.71]), sustained hypertension (OR, 0.52 [95% CI, 0.39-0.70]), and masked hypertension (OR 0.75 [95% CI, 0.62-0.90]). A 1-unit higher log-aldosterone was associated with higher odds of nocturnal hypertension (OR, 1.38 [95% CI, 1.05-1.81]). Neither PRA nor aldosterone was associated with percent dipping, nondipping BP pattern, or white-coat hypertension. Patterns for aldosterone:renin ratio were similar to patterns for PRA. CONCLUSIONS: Suppressed renin activity and higher aldosterone:renin ratios were associated with higher systolic BP and DBP in the office and during the awake and asleep periods as evidenced by ABP monitoring. Higher aldosterone levels were associated with higher DBP, but not systolic BP, in the clinic and during the awake and asleep periods. Further clinical investigation of novel and approved medications that target low renin physiology such as epithelial sodium channel inhibitors and mineralocorticoid receptor antagonists may be paramount in improving hypertension control in African Americans.

6.
Adv Exp Med Biol ; 1278: 125-139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523447

RESUMO

Obesity dramatically increases the risk of numerous conditions, including type 2 diabetes mellitus and other components of the metabolic syndrome. Pro-inflammatory changes that occur in adipose tissue are critical to the pathogenesis of these obesity-induced complications. Adipose tissue is one of the body's largest endocrine organs, and the cells that comprise the adipose tissue immunoenvironment secrete multiple factors (including adipokines and cytokines) that impact systemic metabolism. In particular, immunosuppressive regulatory T cells (Tregs) decline in obesity, partly in response to its complex interaction with adipocytes, and this decline contributes to disruption of the typical homeostasis observed in lean adipose tissue. Although the regulation of Treg differentiation, function, and enrichment is incompletely understood, factors including various cell-surface co-stimulatory molecules, certain lipid species, and cytokines such as PPARγ, adiponectin, and leptin are important mediators. It is also clear that there may be depot-specific differences in Tregs, rendering adipose tissue Tregs distinct from lymphoid or circulating Tregs, with implications on maintenance and functionality. While most of these findings are derived from studies in murine models, comparatively little is known about the human adipose tissue Treg signature, which requires further investigation.


Assuntos
Diabetes Mellitus Tipo 2 , Linfócitos T Reguladores , Adipocinas , Tecido Adiposo , Animais , Humanos , Inflamação , Camundongos , Obesidade
7.
J Endocr Soc ; 4(8): bvaa092, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32803094

RESUMO

Objective: To assess the relationship of physical activity with bone mineral density (BMD) at various sites and examine potential modifying metabolic factors. Methods: Responses from physical activity questionnaires were used to determine total physical activity (PA), moderate physical activity (mod-PA), and sedentary time. Regression analyses were performed to evaluate association of activity traits with insulin sensitivity by euglycemic clamp, adiponectin, C-reactive protein (CRP), and plasminogen activator inhibitor-1 (PAI-1) in 741 healthy subjects. Results: The cohort was relatively sedentary. Activity level was associated with arm, pelvis, and leg BMD in univariate analyses. In multivariate association analyses of arm BMD, only female sex (ß = -0.73, P < 0.0001) and adiponectin (ß = -0.076, P = 0.0091) were significant. Multivariate analyses of pelvis BMD found independent associations with body mass index (BMI) (ß = 0.33, P < 0.0001), adiponectin (ß = -0.10, P = 0.013), female sex (ß = -0.18, P < 0.0001), sedentary time (ß = -0.088, P = 0.034), PA (ß = 0.11, P = 0.01), and mod-PA (ß = 0.11, P = 0.014). Age (ß = -0.10, P = 0.0087), female sex (ß = -0.63, P < 0.0001), BMI (ß = 0.24, P < 0.0001), and mod-PA (ß = 0.10, P = 0.0024) were independently associated with leg BMD. Conclusions: These results suggest that BMD increases with physical activity in the arms, legs, and pelvis and is inversely related to sedentary time in the pelvis and legs; these associations may be modified by age, sex, BMI, and adiponectin, depending on the site, with physical activity being more important to pelvis and leg BMD than arm BMD and sedentary time being important for pelvis BMD. Moreover, we demonstrated that CRP, PAI-1, and insulin sensitivity play a minor role in BMD.

8.
Immunometabolism ; 2(3)2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774894

RESUMO

Background: Obesity is characterized by visceral adipose tissue (AT) inflammation. Immunosuppressive regulatory T cells (Tregs), phagocytic M2-like macrophages, and innate lymphoid cells type 2 (ILC2) control lean AT inflammation to maintain systemic insulin sensitivity, while the loss of these cells in obesity leads to AT inflammation and insulin resistance (IR). Objective: The objective of this study was to determine if weight loss following obesity would correct AT inflammation and systemic metabolism. Results: After six months of high fat diet (HFD) in male C57/Bl6 mice, flow analyses of epidydimal AT stromal vascular fraction (SVF) revealed depleted Tregs by 50%, doubling of CD8+ T cells, tripling of pro-inflammatory M1-like macrophages, and an 80% drop in ILC2 cells associated with changes in pro-inflammatory adipocyte and macrophage gene expression. Despite normalization of body weight, fat, and adipocyte size, mice ingesting 3 months of high-fat diet (HFD) followed by 3 months of chow-diet remained more insulin resistant and glucose intolerant than chow-fed animals. Adipocytes, AT Tregs, CD8+ T cells, ILC2 cells, and M1-like macrophages all failed to normalize with weight loss. Conclusions: Persistent AT inflammation contributes to the maintenance of IR despite body weight and fat normalization in previously obese mice. These findings highlight the importance of obesity prevention to avoid the consequences of "obesogenic memory."

9.
J Clin Endocrinol Metab ; 105(8)2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32436940

RESUMO

CONTEXT: Armadillo repeat containing 5 (ARMC5) on chromosome 16 is an adrenal gland tumor suppressor gene associated with primary aldosteronism, especially among African Americans (AAs). We examined the association of ARMC5 variants with aldosterone, plasma renin activity (PRA), blood pressure, glucose, and glycosylated hemoglobin A1c (HbA1c) in community-dwelling AAs. METHODS: The Jackson Heart Study is a prospective cardiovascular cohort study in AAs with baseline data collection from 2000 to 2004. Kernel machine method was used to perform a single joint test to analyze for an overall association between the phenotypes of interest (aldosterone, PRA, systolic and diastolic blood pressure [SBP, DBP], glucose, and HbA1c) and the ARMC5 single nucleotide variants (SNVs) adjusted for age, sex, BMI, and medications; followed by Baysian Lasso methodology to identify sets of SNVs in terms of associated haplotypes with specific phenotypes. RESULTS: Among 3223 participants (62% female; mean age 55.6 (SD ± 12.8) years), the average SBP and DBP were 127 and 76 mmHg, respectively. The average fasting plasma glucose and HbA1c were 101 mg/dL and 6.0%, respectively. ARMC5 variants were associated with all 6 phenotypes. Haplotype TCGCC (ch16:31476015-31476093) was negatively associated, whereas haplotype CCCCTTGCG (ch16:31477195-31477460) was positively associated with SBP, DBP, and glucose. Haplotypes GGACG (ch16:31477790-31478013) and ACGCG (ch16:31477834-31478113) were negatively associated with aldosterone and positively associated with HbA1c and glucose, respectively. Haplotype GCGCGAGC (ch16:31471193-ch16:31473597(rs114871627) was positively associated with PRA and negatively associated with HbA1c. CONCLUSIONS: ARMC5 variants are associated with aldosterone, PRA, blood pressure, fasting glucose, and HbA1c in community-dwelling AAs, suggesting that germline mutations in ARMC5 may underlie cardiometabolic disease in AAs.


Assuntos
Afro-Americanos/genética , Proteínas do Domínio Armadillo/genética , Glicemia/genética , Pressão Sanguínea/genética , Sistema Renina-Angiotensina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aldosterona/sangue , Estudos Transversais , Jejum/sangue , Feminino , Hemoglobina A Glicada/análise , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Renina/sangue , Adulto Jovem
10.
J Clin Endocrinol Metab ; 105(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31714576

RESUMO

CONTEXT: Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D). OBJECTIVE: To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans. DESIGN, SETTING, AND PARTICIPANTS: A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L-GRS) were evaluated for association with diabetes and indices of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans. RESULTS: Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L-GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method. CONCLUSIONS: Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L-GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Secreção de Insulina/genética , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores/análise , Índice de Massa Corporal , Grupos Étnicos/genética , Feminino , Seguimentos , Genótipo , Humanos , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Fatores de Risco , Estados Unidos/epidemiologia
11.
J Immunol ; 202(8): 2451-2459, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30850480

RESUMO

Macrophages, B cells, and adipocytes are among the adipose tissue (AT) APCs that differentiate and activate naive CD4+ T cells. Mice with adipocyte loss of MHC class II (MHC II) are more insulin sensitive. Because macrophages are professional APCs, mice with genetic myeloid MHC II depletion (myeloid MHC II knockout [mMHCII-/-]) were created and metabolically characterized. FITC+ glucan-coated particles (glucan-encapsulated small interfering RNA [siRNA] particles [GeRPs]) were also used to target MHC II knockout specifically in AT macrophages (ATMs). Mice with total body mMHCII-/- were generated by crossing LyzMCre with H2Ab1 floxed mice. For specific ATM depletion of H2Ab1, GeRPs containing H2Ab1 siRNA were administered to high-fat diet-fed C57BL/6 mice. Unexpectedly, mMHCII-/- mice had loss of both macrophage and adipocyte H2Ab1, one of only two Ag-presenting arms; thus, neither cell could present Ag and activate CD4+ T cells. This inability led to a reduction in AT immunosuppressive regulatory T cells, increased AT CD8+ T cells, and no improvement in systemic metabolism. Thus, with combined systemic myeloid and adipocyte MHC II loss, the impact of ATM-specific alterations in APC activity could not be delineated. Therefore, GeRPs containing H2Ab1 siRNA were administered to specifically reduce ATM H2Ab1 which, in contrast, revealed improved glucose tolerance. In conclusion, loss of either ATM or adipocyte APC function, but not both, improves systemic glucose metabolism because of maintenance of AT regulatory T cells.


Assuntos
Adipócitos/imunologia , Tecido Adiposo/imunologia , Apresentação do Antígeno , Glucose/imunologia , Macrófagos/imunologia , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Glucose/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Macrófagos/citologia , Camundongos , Camundongos Knockout
12.
Obesity (Silver Spring) ; 27(3): 434-443, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30801985

RESUMO

OBJECTIVE: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition. METHODS: Cohorts of mice aged 4 to 8 months ("young") and 18 to 27 months ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps. RESULTS: In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males. CONCLUSIONS: This study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.


Assuntos
Adiposidade/fisiologia , Resistência à Insulina/genética , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Fenótipo
13.
J Diabetes Res ; 2019: 8124563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30719456

RESUMO

Obesity is associated with a state of chronic low-grade inflammation both systemically and within specific tissues, including adipose tissue (AT). In murine models of obesity, there is a shift in the inflammatory profile of the AT immune cells, with an accumulation of proinflammatory M1 macrophages that surround the expanding adipocyte. However, much less is known about the immune cell composition and how to best define AT macrophages in humans. Objective. The goals of the current study were to determine the contribution of macrophages to the stromal vascular fraction (SVF) in lean versus obese human visceral AT (VAT); examine the expression of common M1, M2, and pan macrophage markers; and determine the association of specific macrophage types with known biomarkers of obesity-related cardiometabolic disease. Research Design and Methods. VAT biopsies were obtained from obese (n = 50) and lean (n = 8) patients during elective surgery. Adipocytes and SVF were isolated, and the SVF was subjected to flow cytometry analyses. Results. Our results indicate that VAT macrophages are increased in obesity and associate with biomarkers of CVD but that many macrophages do not fall into currently defined M1/M2 classification system based on CD206 receptor expression levels. Conclusions. VAT macrophages are increased in obese subjects, but the current markers used to define macrophage populations are inadequate to distinguish differences in human obesity. Further studies are needed to delineate the function of AT macrophages in the maintenance and progression of human AT inflammation in obesity.


Assuntos
Inflamação/metabolismo , Gordura Intra-Abdominal/citologia , Macrófagos/citologia , Obesidade/metabolismo , Adiponectina/sangue , Adulto , Feminino , Humanos , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/metabolismo , Leptina/sangue , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade
14.
Diabetes Care ; 42(3): 466-475, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30659075

RESUMO

OBJECTIVE: Components of the adipose tissue (AT) extracellular matrix (ECM) are recently discovered contributors to obesity-related cardiometabolic disease. We identified increased adipocyte expression of ECM-related clusterin (apolipoprotein J) in obese versus lean women by microarray. Our objective was to determine 1) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and 2) how clusterin may contribute to increased risk. RESEARCH DESIGN AND METHODS: We validated increased clusterin expression in adipocytes from a separate group of 18 lean and 54 obese individuals. The relationship of clusterin gene expression and plasma clusterin with IR, cardiovascular biomarkers, and risk of cardiovascular disease (CVD) was then determined. Further investigations in human cultured cells and in aged LDLR-/- mice prone to development of obesity-associated complications were performed. RESULTS: SAd clusterin correlated with IR, multiple CVD biomarkers, and CVD risk, independent of traditional risk factors. Circulating human clusterin exhibited similar associations. In human adipocytes, palmitate enhanced clusterin secretion, and in human hepatocytes, clusterin attenuated insulin signaling and APOA1 expression and stimulated hepatic gluconeogenesis. LRP2 (megalin), a clusterin receptor, highly expressed in liver, mediated these effects, which were inhibited by LRP2 siRNA. In response to Western diet feeding, an increase in adipocyte clusterin expression was associated with a progressive increase in liver fat, steatohepatitis, and fibrosis in aged LDLR-/- mice. CONCLUSIONS: Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver.


Assuntos
Adipócitos/metabolismo , Clusterina/fisiologia , Resistência à Insulina/genética , Insulina/metabolismo , Fígado/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adulto , Animais , Biomarcadores/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Clusterina/genética , Clusterina/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Células Hep G2 , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/genética , Obesidade/metabolismo , Receptores de LDL/genética , Fatores de Risco , Gordura Subcutânea/metabolismo
15.
J Am Heart Assoc ; 7(17): e009890, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30371168

RESUMO

Background Mechanistic studies suggest that aldosterone impairs glucose metabolism. We investigated the cross-sectional associations of aldosterone and plasma renin activity with fasting plasma glucose, insulin resistance ( IR ), ß-cell function, and longitudinal association with incident diabetes mellitus among adults in MESA (the multiethnic study of atherosclerosis) prospective cohort study. Methods and Results Homeostatic model assessment of IR ( HOMA 2- IR ) and HOMA 2-ß were used to estimate IR and ß-cell function, respectively. Incident diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL or anti-diabetic medication use at follow-up. Linear regression was used to examine cross-sectional associations of aldosterone with fasting plasma glucose, HOMA 2- IR and HOMA 2-ß; Cox regression was used to estimate hazard ratios ( HR ) for incident diabetes mellitus with multivariable adjustment. There were 116 cases of incident diabetes mellitus over 10.5 years among 1570 adults (44% non-Hispanic white, 13% Chinese American, 19% Black, 24% Hispanic American, mean age 64±10 years, 51% female). A 100% increase in log-aldosterone was associated with a 2.6 mg/dL higher fasting plasma glucose, 15% higher HOMA 2- IR and 6% higher HOMA 2-ß ( P<0.01). A 1- SD increase in log-aldosterone was associated with a 44% higher risk of incident diabetes mellitus ( P<0.01) with the greatest increase of 142% ( P<0.01) observed in Chinese Americans ( P for interaction=0.09 versus other ethnicities). Similar cross-sectional findings for log-plasma renin activity existed, but log-plasma renin activity was not associated with incident diabetes mellitus after full adjustment. Conclusions Aldosterone is associated with glucose homeostasis and diabetes mellitus risk with graded associations among Chinese Americans and blacks, suggesting that pleiotropic effects of aldosterone may represent a modifiable mechanism in diabetes mellitus pathogenesis with potential racial/ethnic variation.


Assuntos
Aldosterona/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Resistência à Insulina , Sistema Renina-Angiotensina , Renina/metabolismo , Afro-Americanos , Idoso , Americanos Asiáticos , Estudos de Coortes , Diabetes Mellitus Tipo 2/metabolismo , Grupo com Ancestrais do Continente Europeu , Feminino , Hispano-Americanos , Humanos , Incidência , Células Secretoras de Insulina/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos
16.
Clin Endocrinol (Oxf) ; 88(6): 848-855, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29575061

RESUMO

OBJECTIVE: Patients with type 2 diabetes mellitus have an increased risk of fracture despite normal or increased bone mineral density (BMD). Studies on the relationship of glucose homeostasis with BMD phenotypes have been inconclusive because distinguishing the roles of insulin resistance and hyperglycaemia in bone remodelling is challenging. In this study, we sought to define the relationship of site-specific BMD with glucose homeostasis traits and anthropometric traits. DESIGN/PATIENTS/MEASUREMENTS: In a cross-sectional study, we examined 787 subjects from the Mexican-American Coronary Artery Disease (MACAD) cohort who had undergone euglycaemic-hyperinsulinaemic clamps, oral glucose tolerance testing and dual X-ray absorptiometry. Glucose homeostasis traits included insulinogenic index (IGI30), insulin sensitivity (M value), insulin clearance (MCRI), fasting insulin, fasting glucose and 2-hour glucose. Univariate and multivariate analyses were performed to assess the association of glucose homeostasis and anthropometric traits with site-specific BMD. RESULTS: Two-hour glucose was negatively associated with arm BMD in women, which remained significant in multivariate analysis (ß = -.15, P = .0015). Positive correlations between fasting insulin and BMD at weight-bearing sites, including pelvis (ß = .22, P < .0001) and legs (ß = .17, P = .001) in women and pelvis (ß = .33, P < .0001) in men, lost significance after multivariate adjustment. Lean mass exhibited strong independent positive associations with BMD at multiple sites in both sexes. CONCLUSION: Our findings suggest that (i) anabolic effects of insulin might work via mechanical loading from lean mass; (ii) a direct negative effect of increasing glucose might be more prominent at cortical-bone-rich sites in women; and (iii) lean mass is a strong positive predictor of bone mass.


Assuntos
Densidade Óssea/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Absorciometria de Fóton , Adulto , Antropometria , Glicemia/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Teste de Tolerância a Glucose , Homeostase , Humanos , Insulina/metabolismo , Masculino , Análise Multivariada , Adulto Jovem
17.
Circ Cardiovasc Imaging ; 10(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29122843

RESUMO

Cardiometabolic disease, spanning conditions such as obesity to type 2 diabetes mellitus with excess cardiovascular risk, represents a major public health burden. Advances in preclinical translational science point to potential targets across multiple organ systems for early intervention to improve cardiometabolic health. Validation in clinical trials and translation to care would benefit from in vivo diagnostic techniques that facilitate therapeutic advancements. This review provides a state-of-the-art, multimodality perspective spanning the multiple organ systems that contribute to cardiometabolic disease.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Coração/diagnóstico por imagem , Fígado/diagnóstico por imagem , Síndrome Metabólica/diagnóstico por imagem , Imagem Multimodal/métodos , Músculo Esquelético/diagnóstico por imagem , Pâncreas/diagnóstico por imagem , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Metabolismo Energético , Humanos , Fígado/metabolismo , Fígado/fisiopatologia , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Miocárdio/metabolismo , Pâncreas/metabolismo , Pâncreas/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
18.
J Clin Endocrinol Metab ; 102(11): 4124-4135, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938457

RESUMO

Context: Hypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER-ß, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle. Objective: To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women. Methods: Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging. Results: Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (ß = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1. Conclusions: The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.


Assuntos
Receptor beta de Estrogênio/genética , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Fatores Etários , Idoso , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Cloreto de Sódio na Dieta/farmacologia , Adulto Jovem
19.
Am J Prev Med ; 53(5): e165-e174, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28818415

RESUMO

INTRODUCTION: The associations of modifiable lifestyle risk factors with incident diabetes are not well investigated in African Americans (AAs). This study investigated the association of modifiable lifestyle risk factors (exercise, diet, smoking, TV watching, and sleep-disordered breathing burden) with incident diabetes among AAs. METHODS: Modifiable lifestyle risk factors were characterized among 3,252 AAs in the Jackson Heart Study who were free of diabetes at baseline (2000-2004) using baseline questionnaires and combined into risk factor categories: poor (0-3 points), average (4-7 points), and optimal (8-11 points). Incidence rate ratios (IRR) for diabetes (fasting glucose ≥126 mg/dL, physician diagnosis, use of diabetes drugs, or glycosylated hemoglobin A1c ≥6.5%) were estimated using Poisson regression modeling adjusting for age, sex, education, occupation, systolic blood pressure, and BMI. Outcomes were collected 2005-2012 and data analyzed in 2016. RESULTS: Over 7.6 years, there were 560 incident diabetes cases (mean age=53.3 years, 64% female). An average or optimal compared to poor risk factor categorization was associated with a 21% (IRR=0.79, 95% CI=0.62, 0.99) and 31% (IRR=0.69, 95% CI=0.48, 1.01) lower risk of diabetes. Among participants with BMI <30, IRRs for average or optimal compared to poor categorization were 0.60 (95% CI=0.40, 0.91) and 0.53 (95% CI=0.29, 0.97) versus 0.90 (95% CI=0.67, 1.21) and 0.83 (95% CI=0.51, 1.34) among participants with BMI ≥30. CONCLUSIONS: A combination of modifiable lifestyle factors are associated with a lower risk of diabetes among AAs, particularly among those without obesity.


Assuntos
Afro-Americanos , Diabetes Mellitus Tipo 2/diagnóstico , Estilo de Vida , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Dieta , Exercício Físico/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/prevenção & controle , Fatores de Risco , Inquéritos e Questionários
20.
PLoS One ; 11(11): e0166263, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27846285

RESUMO

Reduction in insulin clearance plays an important role in the compensatory response to insulin resistance. Given the importance of this trait to the pathogenesis of diabetes, a deeper understanding of its regulation is warranted. Our goal was to identify metabolic and cardiovascular traits that are independently associated with metabolic clearance rate of insulin (MCRI). We conducted a cross-sectional analysis of metabolic and cardiovascular traits in 765 participants from the Mexican-American Coronary Artery Disease (MACAD) project who had undergone blood sampling, oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, dual-energy X-ray absorptiometry, and carotid ultrasound. We assessed correlations of MCRI with traits from seven domains, including anthropometry, biomarkers, cardiovascular, glucose homeostasis, lipase activity, lipid profile, and liver function tests. We found inverse independent correlations between MCRI and hepatic lipase (P = 0.0004), insulin secretion (P = 0.0002), alanine aminotransferase (P = 0.0045), total fat mass (P = 0.014), and diabetes (P = 0.03). MCRI and apolipoprotein A-I exhibited a positive independent correlation (P = 0.035). These results generate a hypothesis that lipid and adiposity associated traits related to liver function may play a role in insulin clearance.


Assuntos
Apolipoproteína A-I/sangue , Diabetes Mellitus/sangue , Insulina/sangue , Lipase/sangue , Obesidade/sangue , Absorciometria de Fóton , Adiposidade/genética , Adiposidade/fisiologia , Adulto , Estudos Transversais , Diabetes Mellitus/enzimologia , Diabetes Mellitus/patologia , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/genética , Resistência à Insulina/genética , Lipase/genética , Lipídeos/sangue , Fígado/enzimologia , Masculino , Americanos Mexicanos/genética , Obesidade/fisiopatologia
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