RESUMO
The scavenger receptor class B type I (SR-BI), which is expressed in the liver and intestine, plays a critical role in cholesterol metabolism in rodents. While hepatic SR-BI expression controls high density lipoprotein (HDL) cholesterol metabolism, intestinal SR-BI has been proposed to facilitate cholesterol absorption. To evaluate further the relevance of SR-BI in the enterohepatic circulation of cholesterol and bile salts, we studied biliary lipid secretion, hepatic sterol content and synthesis, bile acid metabolism, fecal neutral sterol excretion, and intestinal cholesterol absorption in SR-BI knockout mice. SR-BI deficiency selectively impaired biliary cholesterol secretion, without concomitant changes in either biliary bile acid or phospholipid secretion. Hepatic total and unesterified cholesterol contents were slightly increased in SR-BI-deficient mice, while sterol synthesis was not significantly changed. Bile acid pool size and composition, as well as fecal bile acid excretion, were not altered in SR-BI knockout mice. Intestinal cholesterol absorption was somewhat increased and fecal sterol excretion was slightly decreased in SR-BI knockout mice relative to controls. These findings establish the critical role of hepatic SR-BI expression in selectively controlling the utilization of HDL cholesterol for biliary secretion. In contrast, SR-BI expression is not essential for intestinal cholesterol absorption.
Assuntos
Ácidos e Sais Biliares/metabolismo , Antígenos CD36/fisiologia , Colesterol/metabolismo , Absorção Intestinal , Fígado/metabolismo , Proteínas de Membrana , Receptores Imunológicos , Receptores de Lipoproteínas , Animais , Northern Blotting , Antígenos CD36/genética , Colesterol/sangue , Masculino , Camundongos , Camundongos Knockout , Receptores Depuradores , Receptores Depuradores Classe BRESUMO
INTRODUCTION: Leptin (the product of the human OB gene) is increased in obese individuals, suggesting resistance to its effect. However, there is considerable variability in leptin levels at each level of body mass index (BMI), suggesting that genetic and environmental factors may regulate leptin concentrations. Previous data have suggested that leptin levels are associated with insulin resistance and in a few reports with impaired insulin secretion. We examined whether non-diabetic subjects, with elevated specific insulin and proinsulin levels, had increased leptin levels. METHODS: We used a radioimmunoassay (RIA) to measure serum leptin levels in 197 non-diabetic Mexican Americans and non-Hispanic whites from the San Antonio Heart Study. We also evaluated whether leptin levels were associated with impaired insulin secretion or increased beta cell stress, as evaluated by the fasting proinsulin/insulin ratio. (Higher fasting proinsulin/insulin ratios are thought to reflect impaired insulin secretion.) RESULTS: Leptin levels were significantly correlated with fasting specific insulin (r=0.55, P<0.001) and proinsulin (r=0.57, P<0.001) and inversely with the proinsulin/insulin ratio (r= -0.154, P=0.035) after adjustment for age, gender, ethnicity and 2 h glucose. These associations were similar in men and women and in Mexican Americans and in non-Hispanic whites. After further adjustment for BMI and waist-to-hip ratio (WHR), leptin levels remained significantly correlated with specific insulin (r=0.31, P<0.001) and proinsulin (r=0.24, P<0.001) although the magnitude of the associations were considerably attenuated. CONCLUSION: We conclude that specific insulin and proinsulin are positively related to leptin levels and that these associations are to some degree independent of obesity and body fat distribution. Thus, subjects with increased insulin levels may be relatively resistant to the effects of leptin. However, leptin levels are associated with a decrease in the fasting proinsulin/insulin ratio suggesting that leptin levels are not associated with an impairment in insulin secretion.
Assuntos
Insulina/sangue , Proinsulina/sangue , Proteínas/metabolismo , Glicemia/metabolismo , Composição Corporal , Constituição Corporal , Índice de Massa Corporal , Jejum , Feminino , Hispânico ou Latino , Humanos , Insulina/metabolismo , Secreção de Insulina , Leptina , Modelos Lineares , Masculino , México/etnologia , Pessoa de Meia-Idade , Dobras Cutâneas , Texas , População BrancaRESUMO
OBJECTIVE: Both insulin resistance (IR) and decreased insulin secretion have been shown to predict the development of NIDDM. However, methods to assess insulin sensitivity and secretion are complicated and expensive to apply in epidemiological studies. The homeostasis model assessment (HOMA) has been suggested as a method to assess IR and secretion from the fasting glucose and insulin concentrations. RESEARCH DESIGN AND METHODS: We applied the HOMA model in the 3.5-year follow-up of the Mexico City Diabetes Study. RESULTS: Out of 1,449 subjects, 97 developed diabetes. When modeled separately insulin resistance but not insulin secretion predicted NIDDM. However, when both variables were entered into the same regression model, both increased IR and decreased beta-cell function significantly predicted NIDDM. CONCLUSIONS: We conclude that the HOMA provides a useful model to assess beta-cell function in epidemiological studies and that it is important to take into account the degree of IR in assessing insulin secretion.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Resistência à Insulina , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Adulto , Fatores Etários , Biomarcadores/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Feminino , Seguimentos , Homeostase , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , México , Pessoa de Meia-Idade , Período Pós-Prandial , Estudos Prospectivos , Análise de Regressão , Sensibilidade e Especificidade , Fatores Sexuais , Fatores de TempoRESUMO
OBJECTIVE: Leptin, the product of the human OB gene is increased in obese individuals suggesting resistance to its effect. However, there is variability in leptin levels at each level of body mass index suggesting that genetic and environmental factors other than overall adiposity may regulate leptin concentrations. Moreover, the relation of leptin to various adipose depots may differ. Upper body (or central adiposity) is more metabolically active than peripheral adiposity. METHODS: We examined the relation of serum leptin levels to body fat distribution in 147 non-diabetic subjects from the San Antonio Heart Study. RESULTS: Leptin concentrations in men were significantly correlated with body mass index (BMI) (r = 0.741), waist-to-hip ratio (WHR) (r = 0.567), waist circumference (r = 0.840), hips circumference (r = 0.842) triceps skinfold (r = 0.520) and subscapular skinfold (r = 0.668) but not with subscapular to triceps skinfold (r = 0.185). Leptin concentrations in women were significantly correlated with BMI (r = 0.814), WHR (r = 0.377), waist circumference (r = 0.718), hips circumference (r = 0.779), subscapular skinfolds (r = 0.636) and triceps skinfolds (r = 0.587) but not with the ratio of subscapular to triceps skinfolds (r = 0.184) in women. CONCLUSIONS: Since the associations of leptin with body mass index (a surrogate for overall adiposity), waist circumference (a surrogate for upper body) and hips circumference (a surrogate for lower body adiposity) are similar, we conclude that leptin concentrations are associated with all adipose tissue depots and not disproportionately with upper body or central adiposity.
Assuntos
Tecido Adiposo , Composição Corporal , Hispânico ou Latino , Proteínas/análise , Adulto , Constituição Corporal , Índice de Massa Corporal , Feminino , Humanos , Leptina , Masculino , México/etnologia , Pessoa de Meia-Idade , Obesidade/sangue , Dobras CutâneasRESUMO
Several lines of evidence support an atherogenic role for oxidized low-density lipoprotein (LDL). Previous studies have suggested that although Mexican-Americans have an increased rate of diabetes, obesity, elevated triglyceride levels, and low high-density lipoprotein (HDL) cholesterol levels, their rates of coronary heart disease (CHD) are similar or possibly lower than in non-Hispanic whites. Mexican-Americans have smaller, denser LDL than non-Hispanic whites. On the basis of this latter observation, we postulated that lipid peroxide (LPO) levels would be increased in Mexican-Americans. We examined the oxidizability of plasma in 50 Mexican-Americans and 50 non-Hispanic whites from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease, at baseline and after coincubation with a metal-independent system (2'2'-azobis-2-amidinopropane hydrochloride [AAPH]) and a metal-dependent system (Fe2+/H2O2) of oxidation. LPO levels were measured by a modified fluorimetric assay. Vitamin E and plasma fatty acid composition were also determined. We found significantly higher LPO levels at baseline and after AAPH coincubation in Mexican-Americans than in non-Hispanic whites (baseline, 2.75 +/- .09 v 2.07 +/- .09 micromol/L, P < .001; post-AAPH, 5.49 +/- .14 v 5.07 +/-. .04 micromol/L, P = .037). However, no significant ethnic differences were seen after coincubation with Fe2+/H2O2. Diabetes and cigarette-smoking were also associated with higher LPO levels. Mexican-Americans also had lower levels of vitamin E (the predominant lipid-soluble antioxidant in plasma) than non-Hispanic whites, although these differences only partially explained the differences in susceptibility to oxidation. Plasma fatty acids were similar in Mexican-Americans and non-Hispanic whites, suggesting only small differences in diet composition. We conclude that LPO levels are higher in Mexican-Americans than in non-Hispanic whites, and that these results are only partially related to differences in vitamin E levels.
Assuntos
Peróxidos Lipídicos/sangue , Americanos Mexicanos , Adulto , Antioxidantes/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Técnicas In Vitro , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Fatores de Risco , Texas/epidemiologia , População BrancaRESUMO
Leptin, the product of the OB gene, is increased in obese individuals, suggesting resistance to its effect. We questioned whether subjects with NIDDM have an altered regulation of serum leptin levels. We used a radioimmunoassay to measure serum leptin levels in three groups from the San Antonio Heart Study: 1) 50 Mexican-Americans with NIDDM; 2) 50 nondiabetic Mexican-Americans matched by age and sex to the diabetic Mexican-Americans; and 3) 50 nondiabetic Mexican-Americans matched by age, sex, and BMI to the diabetic Mexican-Americans. Leptin concentrations did not differ significantly by diabetic status. Leptin concentrations were significantly correlated with BMI in all groups (NIDDM women: r = 0.637; nondiabetic women: r = 0.772; NIDDM men: r = 0.849; and nondiabetic men: r = 0.686; all P < 0.001). Leptin levels were higher in women than in men regardless of diabetic status. We concluded that the leptin concentrations were not different in diabetic and nondiabetic subjects and that the association of leptin with obesity was similar in diabetic and nondiabetic subjects.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Americanos Mexicanos , Proteínas/metabolismo , Fatores Etários , Estudos de Coortes , Feminino , Humanos , Leptina , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Valores de Referência , Análise de Regressão , Caracteres Sexuais , Fatores Sexuais , Texas , População BrancaRESUMO
Both insulin resistance and decreased insulin secretion have been hypothesized as precursors of noninsulin-dependent diabetes mellitus (NIDDM). However, there are few data on insulin resistance and secretion in relationship to parental history of diabetes in ethnic groups at different risks for NIDDM. We examined the relationship of fasting insulin (as a marker of insulin resistance) and the ratio of the 30-min change in insulin to the 30-min change in glucose (delta I30/delta G30) during an oral glucose tolerance test (as a marker of insulin secretion) in relation to parental history of diabetes in 1672 nondiabetic Mexican Americans and 894 nondiabetic non-Hispanic whites. A parental history of diabetes was associated with increased fasting insulin concentrations. The association between decreased insulin secretion and parental history of diabetes was not significant. However, when insulin resistance and insulin secretion were included in the same regression model, both fasting insulin (odds ratio = 1.80; 95% confidence interval = 1.17, 2.76) and decreased insulin secretion (odds ratio = 0.70, 95% confidence interval = 0.52, 0.95) were significantly associated with a parental history of diabetes. These results were little changed after adjustment for obesity, body fat distribution, and glucose tolerance. These results were similar in both Mexican Americans and non-Hispanic whites and in both subjects with impaired and those with normal glucose tolerance. A parental history of diabetes in both Mexican Americans and non-Hispanic whites is associated with both increased fasting insulin and decreased delta I30/delta G30. These data suggest that both increased insulin resistance and early decreased insulin secretion in response to an oral glucose challenge may be important factors in the pathogenesis of NIDDM in populations at high and low risk of NIDDM. Our results also emphasize the importance of adjusting for insulin resistance in evaluating insulin secretion.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Hispânico ou Latino , Resistência à Insulina , Insulina/metabolismo , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Feminino , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , México/etnologia , Análise de Regressão , População BrancaRESUMO
OBJECTIVE: To study why Mexican-Americans have a threefold increase in NIDDM relative to non-Hispanic whites. The etiology of NIDDM is still controversial, with both insulin resistance and decreased insulin secretion proposed as precursors of NIDDM. RESEARCH DESIGN AND METHODS: We examined possible ethnic differences in fasting insulin (as a marker of insulin resistance) and change in insulin-to-change in glucose ratio (delta I30:delta G30) during the first 30 min after oral glucose ingestion (as a marker of abnormal whites from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Fasting insulin and delta I30:delta G30 were evaluated as continuous variables. RESULTS: Mexican-Americans had increased insulin concentrations at fasting and 30, 60, and 120 min after an oral glucose load as well as an increased 0- to 30-min increment in insulin and delta I30:delta G30 relative to non-Hispanic whites. These results remained unchanged after adjustment for age, sex, obesity, body fat distribution, and glucose tolerance. CONCLUSIONS: These results suggest that increased insulin resistance rather than decreased insulin secretion is characteristic of nondiabetic Mexican-Americans, a high-risk population for NIDDM.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Resistência à Insulina , Insulina/sangue , Americanos Mexicanos , População Branca , Etnicidade , Jejum , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Fatores de Risco , TexasRESUMO
Recent studies suggest that a relative abundance of small dense LDL is a risk factor for coronary heart disease. We compared LDL size in Mexico City residents (n = 191) and San Antonio Mexican Americans (n = 282), two genetically similar populations that differ markedly in dietary behaviors: in Mexico City approximately 62% of calories are from carbohydrate and approximately 19% from fat, and in San Antonio approximately 40% of calories are from carbohydrate and approximately 40% from fat. Mean LDL size in Mexico City was 258.6 +/- 0.9 A, and in San Antonio, 255.9 +/- 0.6 A (P = .013). After adjustment for the higher triglyceride and lower HDL cholesterol levels (the two most important predictors of LDL size) in Mexico City, LDL size was significantly lower in San Antonio than in Mexico City by -8.33 +/- 0.84 A (P < .001). Our data suggest that the higher triglyceride concentrations in Mexico City residents that are associated with a higher carbohydrate diet may not be associated with atherogenic changes in LDL.
Assuntos
Lipoproteínas LDL/sangue , Americanos Mexicanos , Adulto , Gorduras na Dieta , Feminino , Humanos , Renda , Lipoproteínas LDL/classificação , Masculino , México , Pessoa de Meia-Idade , Análise de Regressão , TexasRESUMO
The relative importance of insulin resistance and abnormal insulin secretion as risk factors for the development of non-insulin-dependent diabetes mellitus (NIDDM) is still controversial. Few data are available on insulin secretion as a risk factor for the development of NIDDM, especially in subjects with normal glucose tolerance. We examined the relation of fasting insulin (as a marker of insulin resistance) and the ratio of change in insulin to change in glucose during the first 30 min after glucose ingestion (delta I30/delta G30) (as a marker of insulin secretion) as predictors of the 7-year development of NIDDM in 714 initially nondiabetic Mexican-Americans. NIDDM developed in 99 subjects. The relative risk of NIDDM increased with higher quartiles of fasting insulin (quartile 1 [low], 1.0; quartile 2, 1.5; quartile 3, 2.0; and quartile 4 [high], 3.7; P < 0.0001) and lower delta I30/delta G30 (quartile 1 [low], 6.9; quartile 2, 1.9; quartile 3, 1.1; quartile 4 [high], 1.0; P < 0.001). Subjects with both increased fasting insulin and decreased delta I30/delta G30 had independent increases in NIDDM incidence (P < 0.001). Further, when we stratified subjects by baseline glucose tolerance, both increased fasting insulin and decreased delta I30/delta G30 significantly predicted NIDDM in subjects with both impaired and normal glucose tolerance at baseline. We conclude that both decreased insulin secretion (as assessed by low delta I30/delta G30) and increased insulin resistance (as assessed by fasting insulin) predict the development of NIDDM in Mexican-Americans, a group previously characterized as having hyperinsulinemia and insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Hispânico ou Latino , Resistência à Insulina , Insulina/metabolismo , Adulto , Glicemia/metabolismo , Constituição Corporal , Índice de Massa Corporal , Estudos de Coortes , Jejum , Feminino , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , México/etnologia , Pessoa de Meia-Idade , Fatores de Risco , TexasRESUMO
Both insulin resistance and decreased insulin secretion have been hypothesized to be precursors of non-insulin-dependent diabetes. An elevated proinsulin concentration reflects abnormal proinsulin processing and could indicate abnormal insulin secretion. We examined fasting insulin (measured by a radioimmunoassay that does not cross-react with proinsulin), as a marker of insulin resistance, and proinsulin and the fasting proinsulin-to-insulin ratio, as markers of impaired proinsulin processing, in 597 nondiabetic Mexican-Americans from the San Antonio Heart Study. Fasting insulin, proinsulin, and the fasting proinsulin-to-insulin ratio were higher in subjects with a parental history of diabetes than in subjects without such a history. These differences remained statistically significant after adjustment for obesity, body fat distribution, and glucose tolerance. A parental history of diabetes in nondiabetic Mexican-Americans is associated with an increase in fasting specific insulin and a disproportionate increase in proinsulin relative to insulin. These data suggest that both increased insulin resistance and abnormal processing of proinsulin are present in offspring of parents with diabetes.