RESUMO
GOALS: We aimed to establish the epidemiological characteristics and documentation of diagnostic workup for gastroparesis (GP). BACKGROUND: No study has used a national database to evaluate the prevalence, demographics, and associated comorbid conditions of GP, and document rates of proper diagnosis. MATERIALS AND METHODS: This was a cross-sectional population-based study using the Explorys Platform to determine the prevalence of GP in a large and diverse population highly representative of the US population and to examine the diagnostic approach of GP. Data collected were individual characteristics from electronic medical records (EMRs) included age, ethnicity/race, sex, diagnostic report for esophagogastroduodenoscopy (EGD) and gastric emptying study (GES). RESULTS: A total of 43,827,910 medical records were surveyed (1999 to 2014), of which 69,950 had a diagnosis of GP, yielding an overall prevalence of 0.16%. We identified 249,930 EMRs with type 1 diabetes mellitus (T1DM), and 2,940,280 EMR's with type 2 diabetes mellitus (T2DM), of which 11,470 (4.59%) and 38,670 (1.31%) EMR's had concurrent GP, respectively. The remainder 19,810 EMRs with a diagnosis of GP were classified as having idiopathic GP. In all three subgroups, women and Caucasians had the highest prevalence of GP. The diagnosis of GP was confirmed by both GES and EGD in 9,950 of patients (14.22%). For patients with T1DM, T2DM, or idiopathic GP, GP was confirmed by both diagnostic tests in 16.8%, 14.0%, and 13.2%, respectively. CONCLUSIONS: Our estimated rates of prevalence of GP in T1DM and T2DM indicate that GP is not a common clinical complication in these populations. Majority of EMRs that indicated a diagnosis of GP did not include any documentation of definitive diagnostic testing (EGD and/or GES).
Assuntos
Gastroparesia/diagnóstico , Gastroparesia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diagnóstico Diferencial , Endoscopia do Sistema Digestório , Feminino , Esvaziamento Gástrico , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Symptoms induced by caloric or non-caloric satiety test meals and gastric myoelectrical activity (GMA) have not been studied in patients with diabetic gastroparesis (DGP) before and after intense glucose management. AIMS: We determined the effects of continuous subcutaneous insulin infusion (CSII) with continuous glucose monitoring (CGM) on GI symptoms, volume consumed, and GMA induced by the caloric meal satiety test (CMST) and water load satiety test (WLST) in DGP. METHODS: Forty-five patients with DGP underwent CMST and WLST at baseline and 24 weeks after CSII with CGM. Subjects ingested the test meals until they were completely full. Visual analog scales were used to quantify pre- and postmeal symptoms, and GMA was recorded with cutaneous electrodes and analyzed visually and by computer. KEY RESULTS: At baseline and 24-week visits, nausea, bloating, abdominal discomfort, and fullness were immediately increased after CMST and WLST (Ps < 0.01). The meal volumes ingested were significantly less than normal controls at both visits in almost one-third of the subjects. After the CMST, the percentage 3 cycle per minute GMA increased and bradygastria decreased compared with WLST (Ps < 0.05). After treatment for 24 weeks meal volumes ingested, postmeal symptoms and GMA were no different than baseline. CONCLUSIONS AND INFERENCES: (a) Satiety test meals elicited symptoms of nausea, bloating, and abdominal discomfort; (b) CMST stimulated more symptoms and changes in GMA than WLST; and (c) CSII with CGM for 24 weeks did not improve symptoms, volumes ingested, or GMA elicited by the two satiety test meals in these patients with diabetic GP. Satiety tests in diabetic gastropresis are useful to study acute postprandial symptoms and GMA, but these measures were not improved by intensive insulin therapy.
Assuntos
Complicações do Diabetes/diagnóstico , Gastroenterologia/métodos , Gastroparesia/diagnóstico , Gastroparesia/etiologia , Insulina/administração & dosagem , Resposta de Saciedade/efeitos dos fármacos , Adolescente , Adulto , Idoso , Automonitorização da Glicemia , Diabetes Mellitus , Feminino , Humanos , Sistemas de Infusão de Insulina , Masculino , Pessoa de Meia-Idade , Complexo Mioelétrico Migratório/efeitos dos fármacos , Adulto JovemRESUMO
Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85-1.64, P = 0.33). CGM time in hypoglycemia (<70 mg/dL) decreased from 3.9% to 1.8% (P<0.0001), time in euglycemia (70-180 mg/dL) increased from 44.0% to 52.0% (P = 0.02), time in severe hyperglycemia (>300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P<0.0001) and volumes of liquid nutrient meals tolerated increased from 420±258 to 487±312 mL (P = 0.05) at 24 weeks. In conclusion, CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis.
Assuntos
Glicemia , Complicações do Diabetes , Gastroparesia/tratamento farmacológico , Gastroparesia/etiologia , Insulina/administração & dosagem , Adolescente , Adulto , Idoso , Feminino , Gastroparesia/diagnóstico , Humanos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Qualidade de Vida , Avaliação de Sintomas , Resultado do Tratamento , Adulto JovemRESUMO
Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes, were evaluated by mining GWAS datasets. eQTL analysis identified 1971 and 2078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2 were identified in both tissues. 62.1 % of top cis-eSNPs were within ±50 kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu ) and identified genetically regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes.
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Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Músculos/metabolismo , Obesidade/genética , Locos de Características Quantitativas/genética , Tecido Adiposo/patologia , Adolescente , Adulto , Negro ou Afro-Americano/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/patologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Obesidade/patologiaRESUMO
Integrative multiomics analyses of adipose and muscle tissue transcripts, S, and genotypes revealed novel genetic regulatory mechanisms of insulin resistance in African Americans.
Assuntos
Tecido Adiposo/metabolismo , Biomarcadores/metabolismo , Negro ou Afro-Americano/genética , Regulação da Expressão Gênica , Resistência à Insulina/genética , Músculo Esquelético/metabolismo , Adolescente , Adulto , Estudos Transversais , Feminino , Teste de Tolerância a Glucose , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , População Branca/genética , Adulto JovemRESUMO
Gastroparesis is a complication of long-standing type 1 and type 2 diabetes mellitus. Symptoms associated with gastroparesis include early satiety, prolonged postprandial fullness, bloating, nausea and vomiting, and abdominal pain. Mortality is increased in patients with diabetic gastroparesis. A subset of patients with diabetic gastroparesis have pylorospasm that results in obstructive gastroparesis. Current treatment approaches include improving glucose control with insulin and prescribing antinauseant drugs, prokinetic agents, and gastric electric stimulation. Future directions include improved diet counseling based on gastric emptying rate, continuous insulin delivery systems with glucose sensor-augmented monitoring, and drugs for correcting gastric neural and electric abnormalities.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/complicações , Gastroparesia/etiologia , Antieméticos/uso terapêutico , Terapia Combinada , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/terapia , Dietoterapia , Terapia por Estimulação Elétrica , Esvaziamento Gástrico/fisiologia , Fármacos Gastrointestinais/uso terapêutico , Gastroparesia/diagnóstico , Gastroparesia/fisiopatologia , Gastroparesia/terapia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêuticoRESUMO
OBJECTIVE: To investigate the association between glycemic variability (GV) and both length of stay (LOS) and 90-day mortality in noncritically ill hospitalized patients. RESEARCH DESIGN AND METHODS: This study retrospectively analyzed 4,262 admissions to the general medicine or surgery services during a 2 year period. Patients with point-of-care glucose monitoring and a minimum of two glucose values per day on average were selected. GV was assessed by SD and coefficient of variation (CV). Data were analyzed with linear and logistic multivariate regression analysis in separate models for SD and CV. Analysis was performed with generalized estimating equations to adjust for correlation between multiple admissions in some individual cases. RESULTS: After exclusions, 935 admissions comprised the sample. Results of adjusted analysis indicate that for every 10 mg/dL increase in SD and 10-percentage point increase in CV, LOS increased by 4.4 and 9.7%, respectively. Relative risk of death in 90 days also increased by 8% for every 10-mg/dL increase in SD. These associations were independent of age, race, service of care (medicine or surgery), previous diagnosis of diabetes, HbA1c, BMI, the use of regular insulin as a sole regimen, mean glucose, and hypoglycemia occurrence during the hospitalization. CONCLUSIONS: Our results indicate that increased GV during hospitalization is independently associated with longer LOS and increased mortality in noncritically ill patients. Prospective studies with continuous glucose monitoring are necessary to investigate this association thoroughly and to generate therapeutic strategies targeted at decreasing GV.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus/sangue , Hiperglicemia/sangue , Hipoglicemia/mortalidade , Pacientes Internados , Tempo de Internação/tendências , Medição de Risco/métodos , Idoso , Diabetes Mellitus/mortalidade , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Humanos , Hiperglicemia/mortalidade , Hipoglicemia/sangue , Unidades de Terapia Intensiva , Masculino , New York/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
PURPOSE: Mentoring is critical for career advancement in academic medicine. However, underrepresented minority (URM) faculty often receive less mentoring than their nonminority peers. The authors conducted a comprehensive review of published mentoring programs designed for URM faculty to identify "promising practices." METHOD: Databases (PubMed, PsycINFO, ERIC, PsychLit, Google Scholar, Dissertations Abstracts International, CINHAL, Sociological Abstracts) were searched for articles describing URM faculty mentoring programs. The RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance) formed the model for analyzing programs. RESULTS: The search identified 73 citations. Abstract reviews led to retrieval of 38 full-text articles for assessment; 18 articles describing 13 programs were selected for review. The reach of these programs ranged from 7 to 128 participants. Most evaluated programs on the basis of the number of grant applications and manuscripts produced or satisfaction with program content. Programs offered a variety of training experiences, and adoption was relatively high, with minor changes made for implementing the intended content. Barriers included time-restricted funding, inadequate evaluation due to few participants, significant time commitments required from mentors, and difficulty in addressing institutional challenges faced by URM faculty. Program sustainability was a concern because programs were supported through external funds, with minimal institutional support. CONCLUSIONS: Mentoring is an important part of academic medicine, particularly for URM faculty who often experience unique career challenges. Despite this need, relatively few publications exist to document mentoring programs for this population. Institutionally supported mentoring programs for URM faculty are needed, along with detailed plans for program sustainability.
Assuntos
Centros Médicos Acadêmicos/organização & administração , Educação Médica/organização & administração , Docentes de Medicina/estatística & dados numéricos , Mentores/estatística & dados numéricos , Grupos Minoritários/estatística & dados numéricos , Humanos , Estados UnidosRESUMO
BACKGROUND: Hispanics in the United States represent diverse racial, ethnic, and socioeconomic groups, and manifest heterogeneous cardiovascular risks including diabetes. It is not known if there are residual differences in the control of diabetes among Hispanic groups given uniform access to diabetes care. OBJECTIVE: To evaluate glucose control differences among Mexicans, Puerto Ricans, and Dominicans receiving substantial diabetes care and support in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. DESIGN: Secondary analysis of data from a randomized trial comparing two treatment strategies: intensive, targeting glycated hemoglobin below 6.0 %, and standard, targeting glycated hemoglobin between 7.0 % and 7.9 %. PARTICIPANTS: Seven hundred and sixteen Hispanic and 6066 non-Hispanic white participants were recruited from 77 clinical sites across the United States and Canada. There were 243 Mexicans, 199 Puerto Ricans, and 150 Dominicans; and 135 of these Hispanic groups were born in the United States. MAIN MEASURE: Glycated hemoglobin RESULTS: Compared to Puerto Ricans, Mexicans were more likely (HR=1.38, CI:0.90-2.10) and Dominicans as likely (HR=1.01, CI:0.66-1.54) to achieve glycated hemoglobin goal in the intensive arm. Participants born in the United States achieved glycated hemoglobin goal at a higher rate than those born elsewhere (HR=1.57, CI:0.99-2.51 in the intensive arm, HR=1.51, CI:0.95-2.43 in the standard arm). These differences were not statistically significant. In the intensive arm, Puerto Ricans (OR=0.47, CI:0.31-0.71), and Dominicans (OR=0.41, CI:0.26-0.66) were less likely than non-Hispanic whites to achieve glycated hemoglobin goal, whereas the difference between non-Hispanic whites and Mexicans was not statistically significant, (OR=0.66, CI:0.43-1.02). CONCLUSIONS: Hispanic groups, given access to comprehensive diabetes care, differed from each other non-significantly and had a variable divergence from non-Hispanic whites in achieving intensive glycated hemoglobin goal. These differences, if confirmed, could be due to such factors as variable acculturation and functional health literacy levels that were not measured in the ACCORD trial, but should be further explored in future studies.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Feminino , Hispânico ou Latino , Humanos , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Porto Rico/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
A reduction of either blood pressure or glycemia decreases some microvascular complications of type 2 diabetes, and we studied here their combined effects. In total, 4733 older adults with established type 2 diabetes and hypertension were randomly assigned to intensive (systolic blood pressure less than 120 mm Hg) or standard (systolic blood pressure less than 140 mm Hg) blood pressure control, and separately to intensive (HbA1c less than 0.060) or standard (HbA1c 0.070-0.079) glycemic control. Prespecified microvascular outcomes were a composite of renal failure and retinopathy and nine single outcomes. Proportional hazard regression models were used without correction for type I error due to multiple tests. During a mean follow-up of 4.7 years, the primary outcome occurred in 11.4% of intensive and 10.9% of standard blood pressure patients (hazard ratio 1.08), and in 11.1% of intensive and 11.2% of standard glycemia control patients. Intensive blood pressure control only reduced the incidence of microalbuminuria (hazard ratio 0.84), and intensive glycemic control reduced the incidence of macroalbuminuria and a few other microvascular outcomes. There was no interaction between blood pressure and glycemic control, and neither treatment prevented renal failure. Thus, in older patients with established type 2 diabetes and hypertension, intensive blood pressure control improved only 1 of 10 prespecified microvascular outcomes. None of the outcomes were significantly reduced by simultaneous intensive treatment of glycemia and blood pressure, signifying the lack of an additional beneficial effect from combined treatment.
Assuntos
Albuminúria/prevenção & controle , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Microcirculação/efeitos dos fármacos , Insuficiência Renal/prevenção & controle , Idoso , Albuminúria/sangue , Albuminúria/etiologia , Albuminúria/fisiopatologia , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Creatinina/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Retinopatia Diabética/sangue , Retinopatia Diabética/etiologia , Retinopatia Diabética/fisiopatologia , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal/sangue , Insuficiência Renal/etiologia , Insuficiência Renal/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A(1C)) achieved during therapy. DESIGN: Post hoc epidemiological analysis of a double 2x2 factorial, randomised, controlled trial. SETTING: Diabetes clinics, research clinics, and primary care clinics. PARTICIPANTS: 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A(1C) concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control. MAIN OUTCOME MEASURES: Severe hypoglycaemia was defined as episodes of "low blood glucose" requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon. RESULTS: The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A(1C) concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A(1C) concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21). CONCLUSIONS: A greater drop in haemoglobin A(1C) concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00000620.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Hemoglobinas Glicadas/metabolismo , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Idoso , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Feminino , Humanos , Hipoglicemia/sangue , Hipoglicemia/terapia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: To determine if baseline subgroups in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality. RESEARCH DESIGN AND METHODS: Exploratory post hoc intention-to-treat comparisons were made between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics. RESULTS: There were few significant interactions between baseline characteristics and effects of intensive versus standard glycemia treatment on mortality: self-reported history of neuropathy (hazard ratio [HR] 1.95, 95% CI 1.41-2.69) versus no history of neuropathy (0.99, 0.79-1.26; P value for interaction 0.0008), higher A1C (A1C >8.5%: HR 1.64, 95% CI 1.22-2.22; A1C 7.5-8.4%: 1.00, 0.75-1.34; A1C <7.5%: 1.00, 0.67-1.50; P value for interaction 0.04), and aspirin use (HR 1.45, 95% CI 1.13-1.85, compared with 0.96, 0.72-1.27, in nonusers; P value for interaction 0.03). CONCLUSIONS: We found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, and previous history of cardiovascular disease. The three baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from intensive regimens for glycemic control. Further research is warranted.
Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Idoso , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Pancreatic neuronal changes associated with beta cell loss in type 1 diabetes mellitus are complex, involving, in part, parasympathetic mechanisms to compensate for preclinical hyperglycemia. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor has been shown to be a useful marker of cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[(18)F]fluorobenzyltrozamicol ([(18)F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. The compound 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), available in a tritiated form, binds to M3 muscarinic receptors on beta cells and is a potential target for assessing pancreatic beta cell mass. In this study, we investigate the feasibility of dual radiotracer analysis in identifying neurofunctional changes that may signify type 1 diabetes mellitus in its early preclinical state. METHODS: Ex vivo determinations of pancreatic uptake were performed in prediabetic nonobese diabetic mice and controls after intravenous injection of [(18)F]FBT or 4-[(3)H]DAMP. Beta cell loss in prediabetic mice was confirmed using immunohistochemical methods. RESULTS: [(18)F]FBT uptake was significantly higher in prediabetic pancreata than controls: 3.22 +/- 0.81 and 2.51 +/- 1.04, respectively (P < 0.03). 4-[(3)H]DAMP uptake was significantly lower in prediabetic pancreata than controls: 0.612 +/- 0.161 and 0.968 +/- 0.364, respectively (P = 0.01). CONCLUSIONS: These data suggest that a combination of radiotracer imaging agents that bind to neuronal elements intimately involved in insulin production may be an effective method of evaluating changes associated with early beta cell loss using PET.
Assuntos
Radioisótopos de Flúor , Células Secretoras de Insulina/patologia , Pâncreas/patologia , Estado Pré-Diabético/diagnóstico , Trítio , Animais , Fluorbenzenos/farmacocinética , Células Secretoras de Insulina/diagnóstico por imagem , Camundongos , Pâncreas/diagnóstico por imagem , Parassimpatolíticos/farmacocinética , Piperidinas/farmacocinética , Estado Pré-Diabético/diagnóstico por imagem , Estado Pré-Diabético/patologia , RadiografiaRESUMO
BACKGROUND: Islet cell adaptation to insulin resistance in type 2 diabetes mellitus may be due in part to increased stimulation of beta cells by the autonomic nervous system. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor correlates with cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[18F]fluorobenzyltrozamicol ([18F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. In this study, we utilize [18F]FBT PET to demonstrate pancreatic cholinergic activity before and after dextrose infusion in nonhuman primates with normal (NGT) and impaired (IGT) glucose tolerance. METHODS: Seven adult female vervet (Chlorocebus aethiops) monkeys were maintained on an atherogenic Western diet. They were divided into two groups: four with NGT and three with IGT. Each subject underwent [18F]FBT PET twice: first, a baseline PET under fasting conditions; and second, PET under fasting conditions but after intravenous infusion of dextrose solution. Quantitative analysis of pancreatic uptake at 60 min post-injection was performed. RESULTS: There was no difference in pancreatic uptake of [18F]FBT on baseline scans between the two groups. Pancreatic uptake of [18F]FBT increased in every subject after dextrose infusion (P = 0.03). On post-dextrose PET scans, pancreatic uptake of [18F]FBT was significantly higher in IGT subjects compared with NGT subjects (P = 0.03). The post-dextrose to pre-dextrose uptake ratios were higher in IGT subjects (P = 0.08). CONCLUSIONS: Acute increases in pancreatic cholinergic activity in vivo were detected in the pancreata of nonhuman primates with NGT and IGT after intravenous dextrose infusion on [18F]FBT PET. In subjects with IGT, this activity was significantly higher, suggesting increased autonomic nervous system stimulation of the pancreatic islets in insulin-resistant subjects.
Assuntos
Intolerância à Glucose/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Glicemia/metabolismo , Chlorocebus aethiops , Feminino , Radioisótopos de Flúor , Fluorbenzenos , Intolerância à Glucose/sangue , Insulina/sangue , Piperidinas , Primatas , Valores de Referência , Triglicerídeos/sangueRESUMO
La Clínica del Pueblo, a health education collaboration between the Maya Angelou Center for Health Equity at Wake Forest University School of Medicine and Qué Pasa Media, Inc., disseminates culturally appropriate health information to the North Carolina (NC) Latino community. The program includes a weekly radio show and corresponding newspaper column addressing four areas: childhood health, adult health, safety, and utilization. The radio show format includes a didactic presentation followed by a call-in question and answer period. Over 200 consecutive weeks of programming have been completed, averaging 11 calls per show. A Latino healthcare resource guide and hotline also provide resource information. Participant demographic information indicates that 50% of the target population comes from Mexico, 60% are women, and 70% of the community is younger than 38 years. There was an increase in the use of the media as a source of health information over the course of the project, from an initial 33% of respondents to 58% in the last survey. Listenership to La Clínica del Pueblo displayed a pronounced increase (18% initial survey to 55% in last survey, P < 0.05). We also observed a statistically significant increase in medical knowledge from initial survey to the last survey (P < 0.001). By multiple regression analysis, we identified 4 predictors of medical knowledge: order of surveys (1 < 3, P < 0.001), education level (P < 0.0001), female gender (P < 0.01) and radio listenership (P < 0.05). The first three variables predicted higher scores; however, radio listening recognition of our radio program was more common among individuals who had lower scores. In conclusion, La Clínica del Pueblo is a model for a novel approach that can reach the Latino community to improve medical knowledge and possibly affect health behaviors in a positive manner.
Assuntos
Centros Médicos Acadêmicos/organização & administração , Educação em Saúde/organização & administração , Hispânico ou Latino , Relações Interinstitucionais , Rádio , Adulto , Comportamento Cooperativo , Competência Cultural , Escolaridade , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Linhas Diretas , Humanos , Masculino , Estado Civil , North Carolina , Fatores de TempoRESUMO
The transport of long-chain fatty acids (LCFAs) across mitochondrial membranes is regulated by carnitine palmitoyltransferase I (CPTI) activity. However, it appears that additional fatty acid transport proteins, such as fatty acid translocase (FAT)/CD36, influence not only LCFA transport across the plasma membrane, but also LCFA transport into mitochondria. Plasma membrane-associated fatty acid binding protein (FABPpm) is also known to be involved in sacrolemmal LCFA transport, and it is also present on the mitochondria. At this location, it has been identified as mitochondrial aspartate amino transferase (mAspAT), despite being structurally identical to FABPpm. Whether this protein is also involved in mitochondrial LCFA transport and oxidation remains unknown. Therefore, we have examined the ability of FABPpm/mAspAT to alter mitochondrial fatty acid oxidation. Muscle contraction increased (P < 0.05) the mitochondrial FAT/CD36 content in rat (+22%) and human skeletal muscle (+33%). By contrast, muscle contraction did not alter the content of mitochondrial FABPpm/mAspAT protein in either rat or human muscles. Electrotransfecting rat soleus muscles, in vivo, with FABPpm cDNA increased FABPpm protein in whole muscle (+150%; P < 0.05), at the plasma membrane (+117%; P < 0.05) and in mitochondria (+80%; P < 0.05). In these FABPpm-transfected muscles, palmitate transport into giant vesicles was increased by +73% (P < 0.05), and fatty acid oxidation in intact muscle was increased by +18% (P < 0.05). By contrast, despite the marked increase in mitochondrial FABPpm/mAspAT protein content (+80%), the rate of mitochondrial palmitate oxidation was not altered (P > 0.05). However, electrotransfection increased mAspAT activity by +70% (P < 0.05), and the mitochondrial FABPpm/mAspAT protein content was significantly correlated with mAspAT activity (r = 0.75). It is concluded that FABPpm has two distinct functions depending on its subcellular location: (a) it contributes to increasing sarcolemmal LCFA transport while not contributing directly to LCFA transport into mitochondria; and (b) its primary role at the mitochondria level is to transport reducing equivalents into the matrix.
Assuntos
Aspartato Aminotransferase Mitocondrial/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Mitocôndrias Musculares/metabolismo , Contração Muscular , Músculo Esquelético/metabolismo , Esforço Físico/fisiologia , Sarcolema/metabolismo , Adulto , Animais , Aspartato Aminotransferase Mitocondrial/genética , Antígenos CD36/metabolismo , Vesículas Citoplasmáticas/metabolismo , Eletroporação/métodos , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Humanos , Masculino , Oxirredução , Ácido Palmítico/metabolismo , Transporte Proteico , Ratos , Ratos Sprague-Dawley , TransfecçãoRESUMO
We examined, in muscle of lean and obese Zucker rats, basal, insulin-induced, and contraction-induced fatty acid transporter translocation and fatty acid uptake, esterification, and oxidation. In lean rats, insulin and contraction induced the translocation of the fatty acid transporter FAT/CD36 (43 and 41%, respectively) and plasma membrane-associated fatty acid binding protein (FABPpm; 19 and 60%) and increased fatty acid uptake (63 and 40%, respectively). Insulin and contraction increased lean muscle palmitate esterification and oxidation 72 and 61%, respectively. In obese rat muscle, basal levels of sarcolemmal FAT/CD36 (+33%) and FABPpm (+14%) and fatty acid uptake (+30%) and esterification (+32%) were increased, whereas fatty acid oxidation was reduced (-28%). Insulin stimulation of obese rat muscle increased plasmalemmal FABPpm (+15%) but not plasmalemmal FAT/CD36, blunted fatty acid uptake and esterification, and failed to reduce fatty acid oxidation. In contracting obese rat muscle, the increases in fatty acid uptake and esterification and FABPpm translocation were normal, but FAT/CD36 translocation was impaired and fatty acid oxidation was blunted. There was no relationship between plasmalemmal fatty acid transporters and palmitate partitioning. In conclusion, fatty acid metabolism is impaired at several levels in muscles of obese Zucker rats; specifically, they are 1) insulin resistant with respect to FAT/CD36 translocation and fatty acid uptake, esterification, and oxidation and 2) contraction resistant with respect to fatty acid oxidation and FAT/CD36 translocation, but, conversely, 3) obese muscles are neither insulin nor contraction resistant at the level of FABPpm. Finally, 4) there is no evidence that plasmalemmal fatty acid transporters contribute to the channeling of fatty acids to specific metabolic destinations within the muscle.
Assuntos
Antígenos CD36/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Músculos/metabolismo , Obesidade/metabolismo , Animais , Feminino , Insulina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Obesidade/fisiopatologia , Ácido Palmítico/metabolismo , Transporte Proteico , Ratos , Ratos Zucker , Distribuição Tecidual , Triglicerídeos/metabolismoAssuntos
Médicos Hospitalares/métodos , Hospitalização , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Cuidados Críticos/métodos , Diabetes Mellitus/tratamento farmacológico , Relação Dose-Resposta a Droga , Medicina Baseada em Evidências/métodos , Humanos , Hiperglicemia/sangue , Hipoglicemia/terapia , Hipoglicemiantes/farmacocinética , Infusões Intravenosas , Injeções Subcutâneas , Insulina/farmacocinética , Avaliação de Processos e Resultados em Cuidados de Saúde , Cuidados Pós-Operatórios/métodos , Guias de Prática Clínica como Assunto , Titulometria/métodosRESUMO
Protein-mediated LCFA transport across plasma membranes is highly regulated by the fatty acid transporters FAT/CD36 and FABPpm. Physiologic stimuli (insulin stimulation, AMP kinase activation) induce the translocation of one or both transporters to the plasma membrane and increase the rate of LCFA transport. In the hypoxic/ischemic heart, intramyocardial lipid accumulation has been attributed to a reduced rate of fatty acid oxidation. However, since acute hypoxia (15 min) activates AMPK, we examined whether an increased accumulation of intramyocardial lipid during hypoxia was also attributable to an increased rate of LCFA uptake as a result AMPK-induced translocation of FAT/CD36 and FABPpm. In cardiac myocytes, hypoxia (15 min) induced the redistribution of FAT/CD36 from an intracellular pool (LDM) (-25%, P<0.05) to the plasma membranes (PM) (+54%, P<0.05). Hypoxia also induced an increase in FABPpm at the PM (+56%, P<0.05) and a concomitant FABPpm reduction in the LDM (-24%, P<0.05). Similarly, in intact, Langendorff perfused hearts, hypoxia induced the translocation of a both FAT/CD36 and FABPpm to the PM (+66% and +61%, respectively, P<0.05), with a concomitant decline in FAT/CD36 and FABPpm in the LDM (-24% and -23%, respectively, P<0.05). Importantly, the increased plasmalemmal content of these transporters was associated with increases in the initial rates of palmitate uptake into cardiac myocytes (+40%, P<0.05). Acute hypoxia also redirected palmitate into intracellular lipid pools, mainly to PL and TG (+48% and +28%, respectively, P<0.05), while fatty acid oxidation was reduced (-35%, P<0.05). Thus, our data indicate that the increased intracellular lipid accumulation in hypoxic hearts is attributable to both: (a) a reduced rate of fatty acid oxidation and (b) an increased rate of fatty acid transport into the heart, the latter being attributable to a hypoxia-induced translocation of fatty acid transporters.
Assuntos
Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Hipóxia/metabolismo , Metabolismo dos Lipídeos , Miocárdio/metabolismo , Proteínas Quinases Ativadas por AMP , Animais , Transporte Biológico , Masculino , Complexos Multienzimáticos/metabolismo , Palmitatos/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Proteico , Ratos , Ratos Wistar , Transdução de Sinais , Frações SubcelularesRESUMO
Recently, fatty acid transport across the plasma membrane has been shown to be a key process that contributes to the regulation of fatty acid metabolism in the heart. Since AMP kinase activation by 5-aminoimidazole-4-carboxamide-1-beta-D: -ribofuranoside (AICAR) stimulates fatty acid oxidation, as well as the expression of selected proteins involved with energy provision, we examined (a) whether AICAR induced the expression of the fatty acid transporters FABPpm and FAT/CD36 in cardiac myocytes and in perfused hearts and (b) the signaling pathway involved. Incubation of cardiac myocytes with AICAR increased the protein expression of the fatty acid transporter FABPpm after 90 min (+27%, P < 0.05) and this protein remained stably overexpressed until 180 min. Similarly, FAT/CD36 protein expression was increased after 60 min (+38%, P < 0.05) and remained overexpressed thereafter. Protein overexpression, which occurred via transcriptional mechanisms, was dependent on the AICAR concentration, with optimal induction occurring at AICAR concentrations 1-5 mM for FABPpm and at 2-8 mM for FAT/CD36. The AICAR (2 h, 2 mM AICAR) effects on FABPpm and FAT/CD36 protein expression were similar in perfused hearts and in cardiac myocytes. AICAR also induced the plasmalemmal content of FAT/CD36 (+49%) and FABPpm (+42%) (P < 0.05). This was accompanied by a marked increase in the rate of palmitate transport (2.5 fold) into giant sarcolemmal vesicles, as well as by increased rates of palmitate oxidation in cardiac myocytes. When the AICAR-induced AMPK phosphorylation was blocked, neither FAT/CD36 nor FABPpm were overexpressed, nor were palmitate uptake and oxidation increased. This study has revealed that AMPK activation stimulates the protein expression of both fatty acid transporters, FAT/CD36 and FABPpm in (a) time- and (b) dose-dependent manner via (c) the AMPK signaling pathway. AICAR also (d) increased the plasmalemmal content of FAT/CD36 and FABPm, thereby (e) increasing the rates of fatty acid transport. Thus, activation of AMPK is a key mechanism regulating the expression as well as the plasmalemmal localization of fatty acid transporters.