RESUMO
BACKGROUND: Chronic alcohol consumption/misuse is a significant risk factor for pneumonia and lung infection leading to the development of chronic pulmonary disorders such as chronic obstructive pulmonary disease (COPD) and lung fibrosis. In this study, we sought to delineate the mechanism of alcohol-associated lung disease. We did so by measuring in vitro mitochondrial, endoplasmic reticulum (ER) oxidative stress in human bronchial epithelial cells (hBECs) treated with ethanol and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters or FAEEs) metabolites. METHODS: Primary hBECs from a normal subject were treated with relevant concentrations of ethanol and its metabolites and incubated at 37°C for 24 h. Viability and cytotoxicity were determined using cell viability and lactate dehydrogenase (LDH) assay kits, respectively. Oxidized glutathione (GSSG) and reduced glutathione (GSH) were measured by colorimetric reaction, and 4-hydroxynenonal (4HNE) by immunohistochemistry. Endoplasmic reticulum stress and dysregulated cellular bioenergetics were determined by western blot analysis. Mitochondrial stress and real-time ATP production rates were determined using a Seahorse Extracellular Flux analyzer. Amelioration of ethanol-induced oxidative/ER stress and mitochondrial energetics was determined using an AMPKα agonist. RESULTS: Human bronchial epithelial cells treated with ethanol, acetaldehyde, and FAEEs showed a concentration-dependent increase in the secretion of LDH, oxidative/ER stress, deactivation of AMPKα phosphorylation and mitochondrial stress (decreased spare respiratory capacity) with concomitant decreases in mitochondrial and glycolytic ATP production rates. FAEEs caused greater cytotoxicity, ER stress, and dysregulated cellular bioenergetics than those ethanol and its oxidative metabolite. AMPKα agonist-pretreated cells significantly ameliorated ethanol-induced oxidative/ER stress, deactivation of AMPKα, and dysregulated cellular bioenergetics. CONCLUSIONS: Findings of this study suggest that ethanol and its metabolites contribute to cytotoxicity, oxidative/ER stress, and dysregulation of cellular bioenergetics in hBECs. The attenuation of ethanol-induced ER/oxidative stress and mitochondrial respiration by an AMPKα agonist may reflect a potential for it to be developed as a therapeutic agent for chronic alcohol-associated lung disease.
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AIMS: Dysregulation of pancreatic fat and lipotoxic inflammation are common clinical findings in alcoholic chronic pancreatitis (ACP). In this study, we investigated a relationship between dysregulated pancreatic lipid metabolism and the development of injury in a chronic ethanol (EtOH) feeding model of hepatic alcohol dehydrogenase 1- deficient (ADH-) deer mice. METHODS: ADH- and hepatic ADH normal (ADH+) deer mice were fed a liquid diet containing 3 % EtOH for three months and received a single gavage of binge EtOH with/without fatty acid ethyl esters (FAEEs) one week before the euthanasia. Plasma and pancreatic tissue were analyzed for lipids including FAEEs, inflammatory markers and adipokines using GC-MS, bioassays/kits, and immunostaining, respectively. Pancreatic morphology and proteins involved in lipogenesis were determined by the H & E staining, electron microscopy and Western blot analysis. KEY FINDINGS: Chronic EtOH feeding in ADH- vs. ADH+ deer mice resulted in a significant increase in the levels of pancreatic lipids including FAEEs, adipokines (leptin and resistin), fat infiltration with inflammatory cells and lipid droplet deposition along with the proteins involved in lipogenesis. The changes exacerbated by an administration of binge EtOH with/without FAEEs in the pancreas of ADH- vs. ADH+ deer mice fed chronic EtOH suggest a metabolic basis for ACP. SIGNIFICANCE: These findings suggest that the liver-pancreatic axis plays a crucial role in etiopathogenesis of ACP, as the increased body burden of EtOH due to hepatic ADH deficiency exacerbates pancreatic injury.
Assuntos
Álcool Desidrogenase , Etanol , Animais , Etanol/toxicidade , Etanol/metabolismo , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Peromyscus/metabolismo , Fígado/metabolismo , Pâncreas/metabolismo , Ácidos Graxos/metabolismo , Inflamação/patologia , Hormônios Pancreáticos/metabolismo , Fenótipo , Ésteres , Adipocinas/metabolismoRESUMO
Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase-deficient (ADH-) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP. Hepatic ADH- and ADH normal (ADH+) deer mice were fed Lieber-DeCarli liquid diet containing 3% (wt/vol) EtOH for 3 mo. One week before the euthanization, chronic EtOH-fed mice were further administered with an oral gavage of binge EtOH with/without FAEEs. Blood alcohol concentration (BAC), pancreatic injury, and inflammatory markers were measured. Pancreatic morphology, ultrastructural changes, and endoplasmic reticulum (ER)/oxidative stress were examined using H&E staining, electron microscopy, immunostaining, and/or Western blot, respectively. Overall, BAC was substantially increased in chronic EtOH-fed groups of ADH- versus ADH+ deer mice. A significant change in pancreatic acinar cell morphology, with mild to moderate fibrosis and ultrastructural changes evident by dilatations and disruption of ER cisternae, ER/oxidative stress along with increased levels of inflammatory markers were observed in the pancreas of chronic EtOH-fed groups of ADH- versus ADH+ deer mice. Furthermore, chronic plus binge EtOH and FAEEs exposure elevated BAC, enhanced ER/oxidative stress, and exacerbated chronic EtOH-induced pancreatic injury in ADH- deer mice suggesting a role of increased body burden of EtOH and its metabolism under reduced hepatic ADH in initiation and progression of ACP.NEW & NOTEWORTHY We established a chronic EtOH feeding model of hepatic alcohol dehydrogenase-deficient (ADH-) deer mice, which mimics several fibroinflammatory features of human alcoholic chronic pancreatitis (ACP). The fibroinflammatory and morphological features exacerbated by chronic plus binge EtOH and FAEEs exposure provide a strong case for metabolic basis of ACP. Most importantly, several pathological and molecular targets identified in this study provide a much broader understanding of the mechanism and avenues to develop therapeutics for ACP.
Assuntos
Álcool Desidrogenase , Pancreatite Alcoólica , Álcool Desidrogenase/metabolismo , Animais , Concentração Alcoólica no Sangue , Ésteres , Etanol , Ácidos Graxos/metabolismo , Peromyscus/metabolismoRESUMO
BACKGROUND: Alcoholic chronic pancreatitis (ACP) is a serious inflammatory disorder of the exocrine pancreatic gland. A previous study from this laboratory showed that ethanol (EtOH) causes cytotoxicity, dysregulates AMPKα and ER/oxidative stress signaling, and induces inflammatory responses in primary human pancreatic acinar cells (hPACs). Here we examined the differential cytotoxicity of EtOH and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters; FAEEs) metabolites in hPACs was examined to understand the metabolic basis and mechanism of ACP. METHODS: We evaluated concentration-dependent cytotoxicity, AMPKα inactivation, ER/oxidative stress, and inflammatory responses in hPACs by incubating them for 6 h with EtOH, acetaldehyde, or FAEEs at clinically relevant concentrations reported in alcoholic subjects using conventional methods. Cellular bioenergetics (mitochondrial stress and a real-time ATP production rate) were determined using Seahorse XFp Extracellular Flux Analyzer in AR42J cells treated with acetaldehyde or FAEEs. RESULTS: We observed concentration-dependent increases in LDH release, inactivation of AMPKα along with upregulation of ACC1 and FAS (key lipogenic proteins), downregulation of p-LKB1 (an oxidative stress-sensitive upstream kinase regulating AMPKα) and CPT1A (involved in ß-oxidation of fatty acids) in hPACs treated with EtOH, acetaldehyde, or FAEEs. Concentration-dependent increases in oxidative stress and ER stress as measured by GRP78, unspliced XBP1, p-eIF2α, and CHOP along with activation of p-JNK1/2, p-ERK1/2, and p-P38MAPK were present in cells treated with EtOH, acetaldehyde, or FAEEs, respectively. Furthermore, a significant decrease was observed in the total ATP production rate with subsequent mitochondrial stress in AR42J cells treated with acetaldehyde and FAEEs. CONCLUSIONS: EtOH and its metabolites, acetaldehyde and FAEEs, caused cytotoxicity, ER/oxidative and mitochondrial stress, and dysregulated AMPKα signaling, suggesting a key role of EtOH metabolism in the etiopathogenesis of ACP. Because oxidative EtOH metabolism is negligible in the exocrine pancreas, the pathogenesis of ACP could be attributable to the formation of FAEEs and related pancreatic acinar cell injury.
Assuntos
Células Acinares/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Etanol/farmacologia , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/citologia , Quinases Proteína-Quinases Ativadas por AMP/efeitos dos fármacos , Quinases Proteína-Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Acetaldeído/farmacologia , Acetil-CoA Carboxilase/efeitos dos fármacos , Acetil-CoA Carboxilase/metabolismo , Células Acinares/metabolismo , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ésteres/farmacologia , Humanos , Mitocôndrias/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 9 Ativada por Mitógeno/metabolismoRESUMO
Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved ß-oxidation of fatty acids). These cells also showed significant ER stress as evidenced by the increased expression for GRP78, IRE1α, and PERK/CHOP arm of unfolded protein response promoting apoptosis and activating p-JNK1/2 and p-ERK1/2 with increased secretion of cytokines. AR42J cells treated with EtOH showed increased oxidative stress, impaired mitochondrial biogenesis, and decreased ATP production rate. However, AMPKα activation by AICAR attenuated EtOH-induced ER/oxidative stress, lipogenesis, and inflammatory responses as well as the formation of FAEEs and restored mitochondrial function in hPACs as well as AR42J cells. Therefore, it is likely that EtOH-induced inactivation of AMPKα plays a crucial role in acinar cell injury leading to pancreatitis. Findings from this study also suggest that EtOH-induced inactivation of AMPKα is closely related to ER/oxidative stress and synthesis of FAEEs, as activation of AMPKα by AICAR attenuates formation of FAEEs, ER/oxidative stress and lipogenesis, and improves inflammatory responses and mitochondrial bioenergetics.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Células Acinares/enzimologia , Retículo Endoplasmático/enzimologia , Etanol/farmacologia , Estresse Oxidativo/fisiologia , Pâncreas/enzimologia , Células Acinares/efeitos dos fármacos , Aciltransferases/metabolismo , Adulto , Células Cultivadas , Relação Dose-Resposta a Droga , Retículo Endoplasmático/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Lipídeos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , FenótipoRESUMO
Chronic excessive alcohol use is a well-recognized risk factor for pancreatic dysfunction and pancreatitis development. Evidence from in vivo and in vitro studies indicates that the detrimental effects of alcohol on the pancreas are from the direct toxic effects of metabolites and byproducts of ethanol metabolism such as reactive oxygen species. Pancreatic dysfunction and pancreatitis development are now increasingly thought to be multifactorial conditions, where alcohol, genetics, lifestyle, and infectious agents may determine the initiation and course of the disease. In this review, we first highlight the role of nonoxidative ethanol metabolism in the generation and accumulation of fatty acid ethyl esters (FAEEs) that cause multi-organellar dysfunction in the pancreas which ultimately leads to pancreatitis development. Further, we discuss how alcohol-mediated altered autophagy leads to the development of pancreatitis. We also provide insights into how alcohol interactions with other co-morbidities such as smoking or viral infections may negatively affect exocrine and endocrine pancreatic function. Finally, we present potential strategies to ameliorate organellar dysfunction which could attenuate pancreatic dysfunction and pancreatitis severity.
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Alcoolismo/complicações , Pancreatite/metabolismo , Animais , Autofagia , Humanos , Secreção de Insulina , Pancreatite/etiologia , Resposta a Proteínas não DobradasRESUMO
Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH-) and ADH normal (ADH+) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH- deer mice fed 3.5% EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH- deer mice fed 3.5% EtOH. Both strains fed 3.5% EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH- deer mice fed 3.5% EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Álcool Desidrogenase/genética , Etanol/toxicidade , Hepatopatias Alcoólicas/genética , Alanina Transaminase/metabolismo , Animais , Concentração Alcoólica no Sangue , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Técnicas de Inativação de Genes , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Chronic alcohol consumption impairs alveolar macrophage's (AM) function and increases risk for developing lung infection and pneumonia. However, the mechanism and metabolic basis of alcohol-induced AM dysfunction leading to lung infection are not well defined, but may include altered ethanol (EtOH) and reactive oxygen species metabolism and cellular energetics. Therefore, oxidative stress, endoplasmic reticulum (ER) stress, the formation of fatty acid ethyl esters [FAEEs, nonoxidative metabolites of EtOH], AMP-activated protein kinase (AMPK) signaling, and phagocytic function were examined in freshly isolated AM incubated with EtOH. METHODS: AMs separated from bronchoalveolar lavage fluid samples obtained from normal volunteers were incubated with EtOH for 24 hours. AMPK signaling and ER stress were assessed using Western blotting, FAEEs by GC-MS, oxidative stress by immunofluorescence using antibodies to 4-hydroxynonenal, and phagocytosis by latex beads. Oxidative stress was also measured in EtOH-treated AMs with/without AMPK activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)] or inhibitor (Compound C), and in AMs incubated with FAEEs. mRNA expression for interleukins (IL-6 and IL-8), monocyte chemoattractant protein (MCP)-1, and transforming growth factor (TGF)-ß was measured in AM treated with EtOH or FAEEs using RT-PCR. RESULTS: EtOH exposure to AM increased oxidative stress, ER stress, and synthesis of FAEEs, decreased phosphorylated AMPK, and impaired phagocytosis. Attenuation or exacerbation of EtOH-induced oxidative stress by AICAR or Compound C, respectively, suggests a link between AMPK signaling, EtOH metabolism, and related oxidative stress. The formation of FAEEs may contribute to EtOH-induced oxidative stress as FAEEs also produced concentration-dependent oxidative stress. An increased mRNA expression of IL-6, IL-8, and MCP-1 by FAEEs is key finding to suggest a metabolic basis of EtOH-induced inflammatory response. CONCLUSIONS: EtOH-induced impaired phagocytosis, oxidative stress, ER stress, and dysregulated AMPK signaling are plausibly associated with the formation of FAEEs and may participate in the pathogenesis of nonspecific pulmonary inflammation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Etanol/efeitos adversos , Etanol/farmacocinética , Macrófagos Alveolares/metabolismo , Fagocitose/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Quimiocina CCL2/biossíntese , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ésteres/metabolismo , Etanol/antagonistas & inibidores , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Humanos , Interleucinas/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ribonucleotídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/biossínteseRESUMO
Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., ß-hydroxybutyrate; ßOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calories) by type 2 diabetic db/db mice for 9â¯days resulted in significant decreases in weight gain (â¼19.5% ↓) and caloric intake (â¼30% ↓). This was accompanied by a transition from macrovesicular-to-microvesicular hepatic steatosis with a modest increase in hepatic TG (â¼37% ↑). Importantly, ethanol increased systemic ßOHB concentration (â¼8-fold ↑) with significant decreases in blood glucose (â¼4-fold ↓) and plasma insulin and HOMA-IR index (â¼3-fold ↓). In addition, ethanol enhanced hepatic ßOHB content (â¼5-fold ↑) and hmgcs2 mRNA expression (â¼3.7-fold ↑), downregulated key gluconeogenic mRNAs (e.g., Pcx, Pck1, and G6pc), and depleted hepatic glycogen (â¼4-fold ↓). Furthermore, ethanol intake led to significant decreases in the mRNA/protein expression and allosteric activation of glycogen synthase (GS) in liver tissues regardless of changes in the phosphorylation of GS, GSK-3ß, or Akt. Together, our findings suggest that ethanol-induced ketonemia may occur in concomitance with significant lowering of blood glucose concentration, which may be attributed to suppression of gluconeogenesis in the setting of glycogen depletion in type 2 diabetes.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/genética , Cetose/metabolismo , Glicogênio Hepático/metabolismo , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Regulação para Baixo , Etanol , Fígado Gorduroso/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Corpos Cetônicos/metabolismo , Cetose/sangue , Cetose/induzido quimicamente , Masculino , Camundongos Knockout , FosforilaçãoRESUMO
AIMS: To develop a risk score, for identifying severe and complex CAD in patients with type 2 diabetes mellitus. METHODS: In this cross sectional study, 179 patients with type 2 diabetes mellitus undergoing coronary angiogram for the evaluation of suspected coronary artery disease (CAD) were recruited at a tertiary-care hospital. Patients were divided into developmental (n=124) and validation (n=55) cohorts. Biochemical and anthropometric parameters were analysed. Predictors of severe and complex CAD (SYNTAX Score>22) were identified by multiple logistic regression analysis. RESULTS: Insulin resistance>3.4 (OR: 21.26, 95% CI: 5.71-79.09), duration of diabetes>5years (OR: 13.50, 95% CI: 3.13-58.25), total cholesterol/HDL-C ratio>5 (OR: 2.75, 95% CI: 0.66-11.55) and waist circumference>96cm (OR: 5.08, 95% CI: 1.27-20.42) were independent predictors of severe and complex CAD, and Manipal Diabetes Coronary Artery Severity Score was developed. CONCLUSIONS: The prediction of severe and complex CAD was achieved with this simple score, and thus enabling effective identification of patients beforehand, who are not likely to be suitable for angioplasty.
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Doença da Artéria Coronariana/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Modelos Estatísticos , Índice de Gravidade de Doença , Idoso , Antropometria , Angiografia Coronária , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/etiologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
AIM: The aim of our study was to compare the angiographic changes in 53 nondiabetic patients, 54 type 2 diabetic patients of less than 5 years of duration, 41 patients with 5-10 years of diabetes, and 27 with more than 10 years of diabetic duration. METHODS: In this cross-sectional study, 175 patients, who underwent coronary angiogram for the evaluation of the coronary artery disease (CAD), were recruited. Based on the angiographic findings, syntax score, vessel score, and coronary collaterals grading were analyzed. The biochemical analysis was done by using the auto analyzer. RESULTS: A significant increase in the mean syntax score (p=0.019), vessel score (p=0.007), and coronary collateral grade (p=0.008) was observed in the patients with 5-10 years of diabetes when compared to those with less than 5 years of diabetic duration. There was no significant difference in the mean syntax score (p=0.979), vessel score (p=0.299), and collateral grade (p=0.842) between the patients with 5-10 years and more than 10 years of diabetes. The difference in the mean syntax score (p=0.791), vessel score (p=0.098), and collateral grade (p=0.661) between the nondiabetic and the patients with less than 5 years of diabetes was not significant. CONCLUSION: A significant structural change in the coronary arteries was found among the patients with 5-10 years of diabetes.
Assuntos
Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Vasos Coronários/diagnóstico por imagem , Diabetes Mellitus Tipo 2/complicações , Medição de Risco/métodos , Idoso , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Progressão da Doença , Feminino , Seguimentos , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Type 2 diabetes mellitus is an important risk factor in the development of coronary artery disease (CAD) and is often associated with severe disease. However, this risk is not uniform, some patients remain free of CAD even after many years of treatment for diabetes. The present study was aimed to identify the factors that are associated with a favorable CAD profile. METHODS: A case-control study of 76 patients with type 2 diabetes mellitus who were on treatment for more than 10 years duration and undergoing a coronary angiogram for the evaluation of clinically suspected CAD at a tertiary care hospital were recruited for the study. The presence and absence of significant CAD was determined after a coronary angiogram. Clinical history, and anthropometric and biochemical parameters were analyzed. Insulin resistance was determined by the Homeostasis Model Assessment. Multiple logistic regressions were done to find out the factors associated for a favorable CAD profile. RESULTS: The difference in HOMA-IR (2.37 ± 0.69 VS 3.77 ± 1.64, p < 0.001) and urine microalbumin (24.15 ± 32.16 VS 82.72 ± 117.70, p = 0.004) were found to be statistically significant among those who did not have CAD when compared to those who had CAD. The difference in lipid profile, HbA1C, fasting blood sugar, BMI, waist hip ratio, waist and hip circumference was not significant. The adjusted odds ratio for insulin resistance less than 2.5 (OR 9.09, 95 % CI 1.91-41.83, p = 0.005), females (OR 7.91, 95% CI 1.55-40.38, p = 0.013) and microalbumin <20 mg/l (OR 4.57, 95% CI 1.17-17.85, p = 0.029) were independently associated with normal coronaries. The adjusted odds ratio for lipid profile, BMI, blood pressure and HbA1C were not significant. CONCLUSIONS: HOMA-IR less than 2.5, microalbuminuria less than 20 mg/l and females are the factors appear to be associated with no apparent CAD.
Assuntos
Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Resistência à Insulina , Albuminúria/epidemiologia , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Proteção , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Relação Cintura-QuadrilRESUMO
BACKGROUND: Insulin resistance (IR) has known to be associated with coronary artery disease (CAD), but the assessment of severity of the CAD based on IR in type 2 diabetes mellitus has not been established in detail. AIMS: The aim of our study was to establish the correlation between IR and the severity of CAD in type 2 diabetes mellitus. MATERIALS AND METHODS: In a cross-sectional study design, 61 consecutive patients with type 2 diabetes mellitus who underwent coronary angiogram for the evaluation of CAD were recruited. Fasting blood glucose, fasting insulin levels, systolic blood pressure and total cholesterol/high density lipoprotein-cholesterol ratio were determined. Homeostasis model assessment-IR (HOMA-IR) was correlated with severity of CAD, which was measured by modified Gensini Score. RESULTS: There was a significant correlation between log HOMA-IR and severity of CAD (r = 0.303, P = 0.009) in diabetic patients. Correlation of the Gensini Score with other known risk factors was not significant. CONCLUSIONS: The results of our study indicate that we might able to predict the severity of CAD by measure of IR.