Insulin resistance and adiposity influence lipoprotein size and subclass concentrations. Results from the Insulin Resistance Atherosclerosis Study

BACKGROUND: Insulin resistance and obesity are associated with a dyslipidemia composed of high levels of triglycerides (TG), low levels of high-density lipoprotein cholesterol (HDL-C), and no change in level of low-density lipoprotein cholesterol (LDL-C). We examined the association of insulin resistance and adiposity with lipoprotein particle size, concentration, and subclass concentrations. METHODS: The Insulin Resistance Atherosclerosis Study is a multicenter cohort study of middle-aged men and women. Lipoprotein lipid concentrations were determined using standard methods. Lipoprotein size, particle concentration, and subclass concentrations were determined using nuclear magnetic resonance technology. Insulin resistance (SI) was determined based on the frequently sampled intravenous glucose tolerance test and the MINMOD program. A higher SI represents less insulin resistance. Fasting insulin, body mass index, waist circumference, and waist/hip ratio were assessed. RESULTS: Among the 1371 participants were 754 women and 617 men; 459 Hispanics, 383 African Americans, and 529 non-Hispanic whites; 437 with type 2 diabetes, 301 with impaired glucose tolerance, and 633 with normal glucose tolerance. The mean (SD) age was 55.5 (8.5) years, body mass index was 29.3 (5.8) kg/m2 , and SI was 1.6 (1.8) units. Adjusted for age, sex, and ethnicity, SI was not associated with LDL-C (r = 0.01); however, S I was associated with LDL size (r = 0.34, P < .001), LDL particle concentration (r = -0.28, P < .001), small LDL (r = -0.34, P < .001), intermediate LDL (r = -0.37, P < .001), and large LDL (r = 0.21, P < .001). In addition, S I was associated with TG (r = -0.36, P < .001), VLDL particles (r = -0.08, P < .01), large VLDL (r = -0.32, P < .001), VLDL size (r = -0.38, P < .001), HDL-C (r = 0.37, P < .001), HDL particles (r = 0.09, P < .001), large HDL (r = 0.31, P < .001), and HDL size (r = 0.33, P < .001). A factor analysis revealed a factor that accounted for 41.4% of the variance across the lipoprotein measures and that was correlated with SI (r = -0.33, P < .001). Similar results of opposing direction were observed for analyses of lipoprotein measures with fasting insulin and adiposity. CONCLUSIONS: The dyslipidemia associated with insulin resistance and obesity includes effects on lipoprotein metabolism that are missed when traditional lipoprotein cholesterol and total TG are examined. Lipoprotein size and subclasses should be examined in studies investigating the roles of insulin resistance and obesity in the pathogenesis and prevention of atherosclerosis.     

Pleiotropic genetic effects on LDL size, plasma triglyceride, and HDL cholesterol in families.

The interrelationships among low density lipoprotein (LDL) particle size, plasma triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) are well established and may involve underlying genetic influences. This study evaluated common genetic effects on LDL size, TG, and HDL-C by using data from 85 kindreds participating in the Genetic Epidemiology of Hypertriglyceridemia (GET) Study. A multivariate, maximum likelihood-based approach to quantitative genetic analysis was used to estimate the additive effects of shared genes and shared, unmeasured nongenetic factors on variation in LDL size and in plasma levels of TG and HDL-C. A significant (P<0.001) proportion of the variance in each trait was attributable to the additive effects of genes. Maximum-likelihood estimates of heritability were 0.34 for LDL size, 0.41 for TG, and 0.54 for HDL-C. Significant (P<0.001) additive genetic correlations (rho(G)), indicative of the shared additive effects of genes on pairs of traits, were estimated between all 3 trait pairs: for LDL size and TG rho(G)=-0.87, for LDL size and HDL-C rho(G)=0.65, and for HDL-C and TG rho(G)=-0.54. A similar pattern of significant environmental correlations between the 3 trait pairs was also observed. These results suggest that a large proportion of the well-documented correlations in LDL size, TG, and HDL-C are likely attributable to the influence of the same gene(s) in these families. That is, the gene(s) that may contribute to decreases in LDL size also contribute significantly to higher plasma levels of TG and lower plasma levels of HDL-C. These relationships may be useful in identifying genes responsible for the associations between these phenotypes and susceptibility to cardiovascular disease in these families.     

Plasma lipid concentrations in nondiabetic African American adults: associations with insulin resistance and the metabolic syndrome

Despite higher rates of cardiovascular disease, African Americans have a more favorable lipid profile. The purpose of the study was to examine the association between plasma lipid concentrations and insulin resistance in African Americans and to determine if insulin resistance is present at a lower triglyceride (TG) threshold than is used for metabolic syndrome criteria. Data were examined on 185 nondiabetic African American men (n = 61) and women (n = 124), mean age, 39.8 years. Measurements included blood pressure, anthropometrics, oral glucose tolerance test, and insulin sensitivity (M) by insulin clamp. The relationship between lipids and insulin sensitivity was analyzed by correlation analysis and by comparing TG levels among tertiles of M. Despite relatively low mean (+/- SD) TG level (87.8 +/- 55.2 mg/dL), there were statistically significant correlations of M with TG (r = -0.23, P < .002), high-density lipoprotein cholesterol (HDL-C; r = 0.19, P < .01), and TG/HDL-C ratio (r = -0.23, P < .002). The correlations were strongest in men. Subjects with TG in an intermediate range (110-149 mg/dL) had insulin resistance equivalent to that of the high-TG group (>/=150 mg/dL). In African Americans, TG levels below the current metabolic syndrome threshold criterion are associated with insulin resistance.     

The association between triglyceride to high-density-lipoprotein cholesterol ratio and insulin resistance in a multiethnic primary prevention cohort

The objective was to explore the clinical utility of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio in predicting insulin resistance (IR) in 4 ethnic groups and the relationship between IR and TG/HDL-C in comparison to that with other lipid measures. Apparently healthy Aboriginals, Chinese, Europeans, and South Asians (N = 784) were assessed for sociodemographics, lifestyle, anthropometry, lipids, glucose, and insulin. The homeostasis model assessment of IR was used as a measure of IR. Compared with other lipid parameters, TG/HDL-C was the highest correlate of the homeostasis model assessment of IR (age and sex adjusted) in Aboriginals (r = 0.499, P < .001), Chinese (r = 0.432, P < .001), Europeans (r = 0.597, P < .001), and South Asians (0.372, P < .001). For a 1-unit increase in TG/HDL-C, the odds of being insulin resistant increased about 4 times (odds ratio [OR], 3.95; 95% confidence interval [CI], 1.86-8.42; P < .001) in Aboriginals, 3.4 times in Chinese (OR, 3.44; 95% CI, 1.79-6.62; P < .001), 1.9 times in Europeans (OR, 1.94; 95% CI, 1.00-3.75; P = .049), and 1.8 times in South Asians (OR, 1.77; 95% CI, 0.91-3.45; P = .094) (age, sex, smoking, physical activity, body mass index, and waist circumference adjusted). Receiver operating characteristic curve analyses revealed areas under the curve (95% CI) of 0.777 (0.707-0.847) in Aboriginals, 0.723 (0.647-0.798) in Chinese, 0.752 (0.675-0.828) in Europeans, and 0.676 (0.590-0.762) in South Asians. Optimal cutoffs (sensitivity, specificity) of TG/HDL-C for identifying individuals with IR were 0.9 (93.0%, 51.9%), 1.1 (71.7%, 61.5%), 1.1 (73.5%, 70.9%), and 1.8 (52.0%, 77.9%) in Aboriginal, Chinese, European, and South Asian individuals, respectively. The TG/HDL-C ratio may be a good marker to identify insulin-resistant individuals of Aboriginal, Chinese, and European, but not South Asian, origin.     

Hypertriglyceridemia is associated with increased insulin resistance in subjects with normal glucose tolerance: evaluation in a large cohort of subjects assessed with the 1999 World Health Organization criteria for the classification of diabetes

The current study retrospectively examined the association between insulin resistance and plasma triglycerides (TG) in a group of subjects with normal glucose tolerance. Among 1,434 subjects consecutively undergoing a standard oral glucose tolerance test (OGTT) between 1993 and 1998, 567 (age, 15 to 78 years) were classified as having a normal glucose tolerance according to the 1999 World Health Organization (WHO) criteria and were selected for the study. Serum insulin was measured by radioimmunoassay (INSI-CTK, Dia Sorin, Saluggia, Italy). Intra-assay and interassay coefficients of variation for the method were less than 4% and less than 8.5%, respectively. Insulin resistance was calculated by a homeostasis model assessment (HOMA(IR) = fasting serum insulin [mU/mL] x fasting blood glucose [mmol/L]/22.5). A very significant correlation was found between HOMA(IR) and plasma TG (r = 0.27, P < 1.02E(-10)). Multiple regression analyses confirmed plasma TG as independent variables explicative of HOMA(IR). When subjects were evaluated according to tertiles of TG, those in the upper two tertiles were older (P <.001) and presented higher body mass index (BMI) values (P <.0001) in comparison to subjects in the lower tertile. A positive trend (analysis of variance [ANOVA]) was found in regard to systolic (P <.05) and diastolic blood pressure (P <.0001), fasting blood glucose (P <.01), fasting serum insulin (P <.0001), and total cholesterol (P <.0001), while a negative trend was found in regard to high-density lipoprotein cholesterol (HDL-C) (P <.0001). Insulin resistance, calculated as HOMA(IR), was higher in the upper two tertiles of TG in comparison to the lower tertile (P <.001 and P <.0001, respectively), with a statistically significant trend for the entire group (first tertile, 1.85 +/- 0.94; second tertile, 2.28 +/- 1.10; third tertile, 2.65 +/- 1.71; ANOVA: P <.0001). In conclusion, this study shows an association between high levels of circulating TG and insulin resistance in patients with normal glucose tolerance seen in an atherosclerosis prevention clinic. This association is also present at levels of plasma TG considered to be normal and is associated with a cluster of cardiovascular risk factors.     

Flow-mediated vasoactivity and circulating adhesion molecules in hypertriglyceridemia: association with small, dense LDL cholesterol particles

BACKGROUND: Endothelial dysfunction is considered one of the earliest events in the process of atherosclerosis, and an impaired vasodilatory response has been reported in patients with dyslipidemias. However, the independent association between hypertriglyceridemia and endothelial dysfunction is controversial, and the relation between endothelium-dependent vasodilation and circulating cell adhesion molecules as markers of endothelial dysfunction has not been fully determined. METHODS: Brachial artery flow mediated vasodilation (FMV) and the soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) were determined after overnight fasting in 16 men with hypertriglyceridemia (age 33 +/- 6 years) and in 16 age-matched healthy men with normal triglycerides and cholesterol. Subjects who smoked and those with known cardiovascular disease, diabetes, hypertension, recent or active infections, or any other disease that could affect leukocyte activation were excluded from the study. RESULTS: Compared with normal subjects, subjects with hypertriglyceridemia showed a higher level of sVCAM-1 and sICAM-1 (both P <.001), a reduced FMV (P <.01), and a smaller LDL particle size (P <.05). FMV had a significant inverse correlation with sVCAM-1 (r = -0.61, P <.001) and sICAM-1 (r = -0.38, P <.03). LDL particle size had a strong, direct association with FMV (r = 0.75, P <.001) and an inverse association with adhesion molecules. By multiple regression analysis, triglycerides (P <.001) and small LDL particle size (P <.002) predicted a reduced FMV. CONCLUSIONS: Serum level of cell adhesion molecules is increased and FMV is impaired in young healthy men with hypertriglyceridemia compared with age-matched men with normal lipid levels. Small, dense LDL particles may play a role in determining endothelial dysfunction in these subjects.     

Low-density lipoprotein particle size, insulin resistance, and proinsulin in a population sample of 58-year-old men

The relationship between insulin sensitivity and low-density lipoprotein (LDL) peak particle size was examined in 104 clinically healthy 58-year-old men recruited from the general population. Insulin sensitivity was measured by the euglycemic hyperinsulinemic clamp method with adjustment for lean body mass. LDL peak particle size was determined by gradient gel electrophoresis, and insulin, proinsulin, and 32,33 split proinsulin were determined by 2-site immunoradiometric assays. The results showed that 16 subjects (15%) had pattern B, with a predominance of small LDL particles. These cases and a small LDL peak particle size were characterized by the features of the insulin resistance syndrome, ie, general and central obesity, elevated diastolic blood pressure, low serum concentrations of high-density lipoprotein (HDL) and apolipoprotein A1 (apoA1), increases in serum triglycerides and circulating insulin peptides, and low insulin-mediated glucose uptake. The correlation between insulin sensitivity and LDL peak particle size was significant (r = .33, P = .001) and independent of obesity. In a traditional multiple regression analysis, LDL peak particle size was independently associated not with insulin-mediated glucose uptake but with circulating triglycerides and HDL cholesterol, which together explained 67% of the variability in LDL particle size (P = .000). Of all insulin peptides, only proinsulin showed an independent relation to LDL peak particle size, but it disappeared after adjustment for other variables. We conclude that a small LDL particle size was associated with insulin resistance among these clinically healthy men, but this was not independent of serum triglycerides and HDL cholesterol. Serum proinsulin was more directly related to LDL particle size than insulin.     

Relationship of regional adiposity to insulin resistance and serum triglyceride levels in nonobese Japanese type 2 diabetic patients

The aim of this study was to investigate the relationships between insulin resistance and regional abdominal fat area, body mass index (BMI), and serum lipid profile in nonobese Japanese type 2 diabetic patients. A total of 63 nonobese Japanese type 2 diabetic patients aged 45 to 83 years were examined. The duration of diabetes was 8.4 +/- 0.8 years. BMI, glycosylated hemoglobin (HbA(1c)) levels, and fasting concentrations of plasma glucose, serum lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides), and serum insulin were measured. The low-density lipoprotein (LDL) cholesterol level was calculated using the Friedewald formula (LDL cholesterol = total cholesterol - HDL cholesterol - 1/5 triglycerides). Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Computed tomography (CT) was used to measure cross-sectional abdominal subcutaneous and visceral fat areas in all the patients. Adipose tissue areas were determined at the umbilical level. Subcutaneous and visceral abdominal fat areas were 136.5 +/- 6.0 and 86.0 +/- 4.1 cm(2), respectively. Univariate regression analysis showed that insulin resistance was positively correlated with subcutaneous (r =.544, P <.001) and visceral (r =.408, P =.001) fat areas, BMI (r =.324, P =.009), HbA(1c) (r =.254, P =.001), serum triglycerides (r =.419, P <.001), and serum LDL cholesterol (r =.290, P =.019) levels and was negatively correlated with serum HDL cholesterol level (r =.254, P =.041). Multiple regression analyses showed that insulin resistance was independently predicted by the areas of subcutaneous (F = 6.76, P <.001) and visceral (F = 4.61, P <.001) abdominal fat and serum triglycerides (F = 8.88, P <.001) level, which explained 36.9% of the variability of insulin resistance. Moreover, the present study demonstrated that whereas BMI was positively correlated with visceral (r =.510, P <.001) and subcutaneous (r =.553, P <.001) fat areas, serum triglyceride level was positively associated with visceral (r =.302, P =.015), but not with subcutaneous (r =.222, P =.074) fat area. From these results, it can be suggested that (1) both subcutaneous and visceral abdominal fat areas are independently associated with insulin resistance and (2) visceral fat area, but not the subcutaneous one, is associated with serum triglyceride levels in our nonobese Japanese type 2 diabetic patients.     

Lipoprotein alterations in hemodialysis: differences between diabetic and nondiabetic patients

Both renal failure and type 2 diabetes may contribute synergistically to the dyslipemia of diabetic renal failure with the development of atherosclerosis as the possible consequence. It has not yet been conclusively evaluated whether diabetic patients with end-stage renal failure under maintenance hemodialysis (HD) show accentuated alterations in plasma lipids and lipoproteins in comparison to nondiabetics under HD. These abnormalities would involve hepatic lipase activity and the regulation of triglyceride-rich lipoprotein metabolism. The purpose of the present study was to evaluate whether type 2 diabetic patients undergoing HD exhibited a lipid-lipoprotein profile different from that of nondiabetic hemodialyzed patients. We compared plasma lipids, apoprotein (apo) A-I and B, and lipoprotein parameters among 3 groups: 25 type 2 diabetics, 25 nondiabetics, both undergoing HD, and 20 healthy control subjects. Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) were isolated by sequential ultracentrifugation. Hepatic lipase activity was measured in postheparin plasma. Both groups of HD patients showed higher triglyceride and IDL cholesterol (P <.001), and lower high-density lipoprotein (HDL) cholesterol (P <.01) and apo A-I (P <.001) levels compared to the control group, even after adjustment for age and body mass index (BMI). However, no differences were found in lipid, lipoprotein, and apoprotein concentrations between diabetic and nondiabetic HD patients, except for high LDL triglyceride content of diabetic HD patients (P <.01). Nondiabetics undergoing HD also presented higher LDL triglyceride levels than controls (P <.05). LDL triglyceride correlated with plasma triglycerides (r = 0.51, P <.001). A lower LDL cholesterol/apo B ratio was found in each group of HD patients in comparison to controls (P <.02). Comparing the diabetic and nondiabetic patients, hepatic lipase activity remained unchanged, but significantly lower than control subjects (P <.001). Hepatic lipase correlated with log-triglyceride (r = -0.31, P <.01), IDL cholesterol (r = -0.41, P <.001), and LDL triglyceride (r = -0.32, P <.01). In conclusion, both diabetic and nondiabetic HD patients shared unfavorable alterations in lipid-lipoprotein profile not different between them but different from a healthy control group. The only difference between the groups of HD patients was a significant LDL triglyceride enrichment, which correlated negatively with hepatic lipase activity. Lipoprotein abnormalities in HD patients would enhance their risk for the development of atherosclerosis.     

In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients: is cellular insulin resistance caused by glucotoxicity in vivo?

Chronic hyperglycemia promotes the development of insulin resistance. The aim of this study was to investigate whether cellular insulin resistance is secondary to the diabetic state in human type 2 diabetes. Subcutaneous fat biopsies were taken from 3 age-, sex-, and body mass index (BMI)-matched groups with 10 subjects in each group: type 2 diabetes patients with either good (hemoglobin A(1c) [HbA(1c)] < 7%, G) or poor (HbA(1c) > 7.5%, P) metabolic control and healthy control subjects (C). Insulin action in vitro was studied by measurements of glucose uptake both directly after cell isolation and following a 24-hour incubation at a physiological glucose level (6 mmol/L). The relationship with insulin action in vivo was addressed by employing the euglycemic clamp technique. Freshly isolated fat cells from type 2 diabetes patients with poor metabolic control had approximately 55% lower maximal insulin response (1,000 microU/mL) on glucose uptake (P <.05) compared to C. Cells from P were more insulin-resistant (P <.05) than cells from G at a low (5 microU/mL) but not at a high (1,000 microU/mL) insulin concentration, suggesting insulin insensitivity. However, following 24 hours of incubation at physiological glucose levels, insulin resistance was completely reversed in the diabetes cells and no differences in insulin-stimulated glucose uptake were found among the 3 groups. Insulin sensitivity in vivo assessed with hyperinsulinemic, euglycemic clamp (M-value) was significantly associated with insulin action on glucose uptake in fresh adipocytes in vitro (r = 0.50, P <.01). Fasting blood glucose at the time of biopsy and HbA(1c), but not serum insulin, were negatively correlated to insulin's effect to stimulate glucose uptake in vitro (r = -0.36, P =.064 and r = - 0.41, P <.05, respectively) in all groups taken together. In the in vivo situation, fasting blood glucose, HbA(1c), and serum insulin were all negatively correlated to insulin sensitivity (M-value; r = -0.62, P<.001, r= -0.61, P<.001, and r = -0.56, p <.01, respectively). Cell size, waist-to-hip ration (WHR), and BMI correlated negatively with insulin's effect to stimulate glucose uptake both in vitro (r = -0.55, P <.01, r = -0.54, P <.01, and r = -0.43, P <.05, respectively) and in vivo (r = -0.43, P <.05, r = -0.50, P <.01, and r = -0.36, P <.05, respectively). Multiple regression analyses revealed that adipocyte cell size and WHR independently predicted insulin resistance in vitro. Furthermore, insulin sensitivity in vivo could be predicted by fasting blood glucose and serum insulin levels. We conclude that insulin resistance in fat cells from type 2 diabetes patients is fully reversible following incubation at physiological glucose concentrations. Thus, cellular insulin resistance may be mainly secondary to the hyperglycemic state in vivo.     

Assessment of LDL particle size by triglyceride/HDL-cholesterol ratio in non-diabetic, healthy subjects without prominent hyperlipidemia

Small, dense low-density lipoprotein (LDL) is an atherogenic lipoprotein because of its susceptibility to oxidative modification. However, evaluating LDL size requires highly sophisticated techniques. We investigated potentially convenient biochemical parameters for assessing the presence of small, dense LDL. Thirty-nine male subjects, who had been involved in a work-site health promotion program, were recruited. Subjects were divided into two groups: normal LDL size (> 25.5 nm, Normal LDL group) and small LDL (相似文献   

Normal triglyceride levels despite insulin resistance in African Americans: role of lipoprotein lipase

Abstract Lipoprotein lipase (LPL), the enzyme responsible for hydrolyzing triglyceride (TG) in plasma lipoproteins, is a key regulator of plasma TG levels. In Caucasians, postheparin-LPL (PH-LPL) activity is impaired in the presence of insulin resistance and leads to elevated TG levels. However, African Americans are often both insulin-resistant and normotriglyceridemic. But in African Americans, the effect of insulin resistance on PH-LPL activity has not been studied. In African Americans, if insulin resistance is not associated with a decrease in PH-LPL activity, this could account for the simultaneous presence of insulin resistance and normotriglyceridemia. Therefore, our goal was to determine in African Americans the relationship between insulin resistance and PH-LPL activity. In a cross-sectional study of 107 nondiabetic African Americans (57 men and 50 women; age mean +/- SD, 35 +/- 8 years, range 22-50 years; body mass index 31.6 +/- 7.9 kg/m 2 , range 18.5-54.7 kg/m 2 ), fasting TG levels and PH-LPL activity were determined. Visceral adipose tissue was measured by abdominal computed tomographic scan. Insulin resistance was determined by the insulin sensitivity index ( S I ). Subjects were divided into tertiles by S I . The range of S I in each tertile was 12.75 to 3.99, 3.87 to 2.20, 2.06 to 0.17 mU . L -1 . min -1 . Insulin resistance was defined as being in the third tertile. TG levels in the men and women were 82.2 +/- 35.5 versus 56.4 +/- 30.1 mg/dL, P < .001. There were no sex difference in PH-LPL activity (8.9 +/- 2.5 vs 9.6 +/- 3.2 mmol/h per liter, P = .30) or S I (3.65 +/- 2.59 vs 3.23 +/- 1.89 L . mU -1 . min -1 , P = .49). Although 47% of the subjects were obese, only 4% of subjects had hypertriglyceridemia (TG > or =150 mg/dL). By 2 separate analyses, PH-LPL was a major determinant of TG levels. First, there was a significant inverse correlation between PH-LPL activity and TG levels (men: r = -0.46, P < .001; women: r = -0.28, P = .046). Second, in the multiple regression analysis with TG as the dependent variable and PH-LPL, age, sex, S I , and visceral adipose tissue as independent variables, adjusted R 2 was 54% and the effect of PH-LPL on TG levels was highly significant( P < .001). However, insulin resistance did not appear to influence PH-LPL activity. This is demonstrated in 3 ways: first, PH-LPL activity was not different in the S I tertiles (9.10 +/- 2.75, 9.52 +/- 2.91, 9.13 +/- 2.89 mmol/h per liter, P = .78); the correlation between PH-LPL and S I was not significant (men: r = 0.09, P = .51; women: r = -0.03, P = .78), and a multiple regression with PH-LPL as the dependent variable and age, S I , body mass index, and sex as independent variables, adjusted R 2 was <2% and the contribution of S I was not significant ( P = .53). Hence, in African Americans, increased PH-LPL activity is associated with a decrease in TG levels. The lack of an effect of insulin resistance on PH-LPL could allow LPL to clear TG even in the presence of insulin resistance and explain the coexistence of insulin resistance and normotriglyceridemia in African Americans.     

Lipoprotein lipase activator NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin-induced diabetic rats

NO-1886 is a lipoprotein lipase (LPL) activator. Administration of NO-1886 results in an increase in plasma high-density lipoprotein cholesterol (HDL-C) and a decrease in plasma triglyceride (TG) levels. The aim of this study was to ascertain whether NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin (STZ)-induced diabetic rats. Administration of NO-1886 resulted in increased plasma HDL-C levels and decreased TG levels without affecting total cholesterol and glucose levels in the diabetic rats. NO-1886 dose-dependently decreased liver TG contents and cholesterol contents, resulting in improvement of fatty liver. NO-1886 also reduced plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that accompany fatty liver. The liver cholesterol contents were inversely correlated with plasma HDL-C levels (r = -0.5862, P <.001) and were positively correlated with plasma TG levels (r = 0.4083, P <.003). The liver TG contents were inversely correlated with plasma HDL-C levels (r = -0.6195, P <.001) and were positively correlated with plasma TG levels (r = 0.5837, P <.001). There was no correlation between plasma cholesterol levels, and cholesterol and TG contents in liver. These results indicate that reducing plasma TG levels and elevating in HDL-C levels may result in improving fatty liver.     

Low density lipoprotein cholesterol, lipoprotein(a), and apo(a) isoforms in the elderly: relationship to fasting insulin. Associazione Medica Sabin

BACKGROUND AND AIM: Insulin resistance/hyperinsulinemia are often associated with aging and could play an important role in the development of glucose intolerance and dyslipidemia in the elderly. We investigated the relationship between plasma fasting insulin with total cholesterol (TC) and low density lipoprotein LDL cholesterol (LDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)] levels apolipoprotein (a) [apo (a)] isoforms in 100 free-living "healthy" octo-nonagenarians. METHODS AND RESULTS: Fasting insulin was positively correlated with TG, whereas a negative relation was found with TC and LDL-C (r = -0.29 and r = -0.28 respectively; p < 0.01), LDL-C/apo B, HDL-C and apo A-I levels. Fasting insulin was also inversely correlated with Lp(a) levels (r = -0.22; p < 0.03), whereas the latter were significantly related with TC and LDL-C (r = 0.30 and r = 0.31; p < 0.005), TG (r = 0.21; p < 0.05) and apo B (r = 0.26; p < 0.02). There was a negative relation between Lp(a) levels and apo(a) isoforms: the greater the apo(a) molecular weight, the lower the Lp(a) level (p < 0.0001). Fasting insulin increased with apo(a) size, though the difference in insulin levels among apo(a) isoforms was not significant (p = 0.4). Multiple regression analysis showed that fasting insulin was the best predictor of LDL-C (R2 = 0.14; p = 0.002) irrespective of age, gender, BMI, waist circumference and TG, while apo(a) isoform size, BMI and waist circumference were related with Lp(a) irrespective of TC and LDL-C, TG and apo B (R2 = 0.35 to 0.37; p < 0.0001). CONCLUSIONS: These results suggest that fasting insulin levels significantly influence LDL-C metabolism in old age. Lp(a) levels seem to be very strongly related to genetic background, although an indirect relation with insulin through adiposity and/or other associated lipid abnormalities cannot be ruled out.     

Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content

Insulin resistance is associated with increased circulating lipids and skeletal muscle lipid content. Chronic nicotinic acid (NA) treatment reduces insulin sensitivity and provides a model of insulin resistance. We hypothesized that the reduction in insulin sensitivity occurs via elevation of circulating nonesterified fatty acids (NEFAs) and an increase in intramyocellular lipid (IMCL). A total of 15 nondiabetic males (mean age 27.4 +/- 1.6 years) were treated with NA (500 mg daily for 1 week, 1 g daily for 1 week). Insulin sensitivity (glucose infusion rate [GIR]) was determined pre- and post-NA by euglycemic-hyperinsulinemic clamp. Substrate oxidation was determined by indirect calorimetry. Skeletal muscle lipid was assessed by estimation of long-chain acyl-CoA (LCACoA) and triglyceride (TG) content and by (1)H-magnetic resonance spectroscopy quantification of IMCL (n = 11). NA reduced GIR (P =.03) and nonoxidative glucose disposal (P <.01) and increased fasting NEFAs (P =.01). The decrease in GIR related significantly to the increase in fasting NEFAs (r(2) =.30, P =.03). The intrasubject increase in basal and clamp fat oxidation correlated with the decrease in GIR (r(2) =.45, P <.01 and r(2) =.63, P <.01). There were no significant changes in muscle LCACoA, TG, or IMCL content. Therefore, induction of insulin resistance by NA occurs with increased availability of circulating fatty acids to muscle rather than with increased muscle lipid content.     

The triglyceride/high-density lipoprotein cholesterol ratio, the small dense low-density lipoprotein phenotype, and ischemic heart disease risk

This study investigated the relevance of using the plasma triglyceride to high-density lipoprotein cholesterol ratio (Log TG/HDL-C) for the prediction of the small dense lowdensity lipoprotein (LDL) phenotype and the risk of ischemic heart disease (IHD). Analyses were based on data from the Quebec Cardiovascular Study in a cohort of 2072 men free of IHD at baseline, among whom 262 had a first IHD event (coronary death, non fatal myocardial infarction and unstable angina) during a 13-year follow-up period. LDL particle size phenotype was characterized using 2-16% polyacrylamide gradient gel electrophoresis (PAGGE) of whole plasma. There were significant associations between the Log TG/HDL-C ratio and features of LDL size phenotype such as the proportion of LDL with a diameter <255A (r = 0.43, p < 0.001) and LDL peak particle size (r = -20.55, p < 0.001). However, the Log TG/HDL-C ratio brought no additional value (p a yen 0.1) in predicting the small dense LDL phenotype (area under the receiver operating curve (AUROC = 71.9%) compared to TG alone (AUROC = 71.2%) or to a combination of Log TG and HDL-C (AUROC = 72.4%) after multivariate adjustment for non lipid risk factors. Finally, elevations in the Log TG/HDL-C ratio did not improve the discrimination of incident IHD cases from non IHD cases compared to the use of plasma TG levels alone (p = 0.5) or a combination of the individual TG and HDL-C values (p = 0.5). The Log TG/HDL-C ratio does not improve our ability to identify individuals with the small dense LDL phenotype compared to plasma TG levels alone. The Log TG/HDLC is also not superior to plasma TG levels alone in predicting IHD risk in men of the QuA(c)bec Cardiovascular Study.     

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic, human immunodeficiency virus (HIV)-infected patients with and without lipodystrophy. We studied 18 HIV-infected patients with lipodystrophy (LIPO) on antiretroviral therapy and 25 HIV-infected patients without lipodystrophy (controls) of whom 18 were on antiretroviral therapy and 7 were not. Posthepatic insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU.m-2 .min-1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting insulin (130%, P < .001), impaired insulin sensitivity index (M value, -29%, P < .001), and reduced MCRi (-17%, P < .01). Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P < .02 and r = -0.68, P < .002) and positively with M value (r = 0.63, P < .01 and r = 0.65, P < .004). In controls, MCRi correlated inversely with fasting insulin (r = -0.47, P < .02) and positively with M value (r = 0.57, P < .004); however, the correlations between HEXi and these parameters were insignificant (P > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy.     

Associations between the fatty acid content of triglyceride, visceral adipose tissue accumulation, and components of the insulin resistance syndrome

Many factors are involved in the development of the insulin resistance syndrome, such as visceral obesity and the type of dietary fat. The main purpose of this study was to investigate the relationships between fatty acid content of triglyceride (TG), visceral adipose tissue (AT) accumulation, and metabolic components of the insulin resistance syndrome in a group of 97 Caucasian men with a mean age of 45.1 +/- 7.2 years (29 to 63 years). To reach these objectives, Spearman correlations, group comparisons, and stepwise multiple regression analyses were performed. The proportion of palmitic acid (16:0) in the TG fraction was positively associated with plasma fasting insulin (r =.25, P =.03), diastolic (r =.45, P <.001), and systolic (r =.29, P =.003) blood pressure. On the other hand, the proportion of alpha-linolenic acid (18:3n-3) was associated negatively with apolipoprotein (apo) B (r = -.29, P =.005) and positively with low-density lipoprotein (LDL) diameter (r =.29, P =.007), while the proportion of gamma-linolenic acid (18:3n-6) was associated negatively with plasma TG (r = -.33, P =.003), diastolic (r = -.29, P =.01), and systolic (r = -.35, P =.002) blood pressure and plasma fasting insulin (r = -.37, P =.0005) and positively with high-density lipoprotein (HDL)(2)-cholesterol (r =.27, P =.01) and LDL diameter (r =.25, P =.02). Stepwise multiple regression analyses were conducted to determine the contribution of visceral AT, body fat mass, and the fatty acid content of TG to the variance of metabolic variables studied. It was found that visceral AT contributed significantly to the variance in plasma TG (R(2) = 20.7%, P <.0001), apo B (R(2) = 9.0%, P =.007), HDL(2)-cholesterol (R(2) = 17.9%, P <.0001), LDL diameter (R(2) = 4.9%, P =.02), and area under the glucose curve (AUC-glucose) (R(2) = 8.2%, P =.006). On the other hand, body fat mass contributed significantly to the variance in fasting insulin (R(2) = 19.7%, P <.0001) and diastolic (R(2) = 6.8%, P =.007) and systolic (R(2) = 10.5%, P =.01) blood pressure. At least one fatty acid made a significant contribution to the variance of each metabolic variable studied. In fact, the proportion of 18:3n-6 contributed significantly to the variance in both TG (R(2) = 8.9%, P = 0.007) and HDL(2)-cholesterol (R(2) = 6.0%, P =.01). Moreover, 18:3n-3 contributed to the variance of apo B (R(2) = 7.0%, P =.02), while 18:3n-6 made the largest contribution to the variance of LDL diameter (R(2) = 7.6%, P =.02). Finally, 16:0 significantly contributed to the variance of AUC-glucose (R(2) = 11.4%, P =.0003), diastolic (R(2) = 25.2%, P <.0001), and systolic (R(2) = 6.8%, P =.002) blood pressure. In summary, results of this study suggest that the fatty acid content of TG is associated with many metabolic variables of the insulin resistance syndrome independently of body fat mass or visceral AT accumulation.     

Plasma plasminogen activator inhibitor-I is associated with plasma leptin irrespective of body mass index, body fat mass, and plasma insulin and metabolic parameters in premenopausal women.

Leptin, the satiety hormone expressed almost exclusively in adipose tissue, is a marker of body fat accumulation in humans. Recent studies have shown that plasminogen activator inhibitor-1 (PAI-1), a prothrombotic factor associated with atherosclerosis complications, is also produced in adipose tissue. The objective of the present study was to determine whether PAI-1 antigen plasma concentrations are associated with leptin plasma levels or the body fat mass (FM) independently of the variables known to influence PAI-1 production. Sixty-one nondiabetic women aged 18 to 45 years with a wide range of values for the body mass index ([BMI] 18.1 to 37.7 kg/m2) were evaluated for (1) body FM and fasting plasma levels of (2) PAI-1 antigen, (3) PAI-1 activity, (4) leptin, (5) insulin, (6) blood glucose, and (7) lipids (cholesterol, high-density lipoprotein [HDL]-cholesterol, and triglycerides [TG]). Body FM and fat-free mass (FFM) were estimated during fasting conditions by the bioimpedance analysis (BIA) method using a tetrapolar device. Body fat distribution was evaluated by the waist circumference and the waist to hip ratio (WHR). FM was directly associated with both PAI-1 antigen (r = .585, P < .001) and PAI-1 activity (r = .339, P < .001). Seemingly, leptin was positively related to both PAI-1 antigen (r = .630, P < .001) and PAI-1 activity (r = .497, P < .001). Moreover, both PAI-I antigen and PAI-1 activity were directly correlated with FFM (r = .285, P < .05, and r = .336, P < .01, respectively), BMI (r = .594, P < .001, and r = .458, P < .001, respectively), and WHR (r = .510, P < .001, and r = .391, P < .005, respectively). Insulin was directly related to PAI-1 antigen (r = .540, P < .001), PAI-1 activity (r = .259, P < .05), leptin (r = .447, P < .001), and FM (r = .435, P < .001). The association between PAI-1 antigen (dependent variable) and leptin or FM was tested by a stepwise regression model simultaneously including leptin, FM, BMI, WHR, age, FFM, and fasting insulin, blood glucose, TG, cholesterol, and HDL-cholesterol as independent variables. PAI-1 antigen maintained a significant positive independent relationship only with leptin (t = 2.923, P < .01), insulin (t = 3.489, P < .001), and fasting blood glucose (t = 2.092, P < .05), and a negative independent relationship with HDL-cholesterol (t = -2.634, P < .05). In conclusion, the strong relationship between PAI-1 antigen and leptin irrespective of other variables known to influence these factors seems to indicate that leptin per se may potentially increase PAI-1 plasma concentrations in obese subjects.     

Relation of insulin to left ventricular geometry and function in African American and white hypertensive adults: the HyperGEN study

BACKGROUND: It has been suggested that the trophic effects of insulin may contribute to left ventricular (LV) hypertrophy in hypertension, but few population-based data exist to assess the potential impact of insulin level on LV structure or systolic function. METHODS: Fasting plasma insulin levels (log-transformed) in 1,542 nondiabetic African American or white hypertensive participants in the Hypertension Genetic Epidemiology Network (HyperGEN) study were compared to indices of LV geometry and function, with adjustment for potential confounders (age, sex, ethnicity, blood pressure (BP), body mass index, height and antihypertensive drugs). RESULTS: In simple correlation analysis, a weak positive relation (r = 0.078, P =.002) was found between LV mass and insulin, principally due to positive correlations (r = 0.22 and 0.50) of both variables to body mass index. Multivariate analysis, adjusting for age, sex, ethnicity, body size, systolic BP, and antihypertensive drugs revealed a modest negative relation between insulin and LV mass (r = -0.08, P =.001) due to a negative relationship between insulin with LV chamber size (r = - 0.10, P <.001) and no significant relation to LV wall thicknesses. These results were confirmed in additional analysis controlling for a positive relation (r =.19, P <.0001) of insulin to heart rate, and the relation with insulin became slightly more negative when LV mass was indexed for height(2.7) (r = -0.13, P <.001). After adjustment for covariates, there were no significant relations of insulin to LV ejection fraction or stress-corrected midwall shortening; however, insulin was negatively related to stroke volume (r = -0.12, p < 0.001) and was weakly related positively to relative wall thickness (r =.053) (P =.04). CONCLUSIONS: After adjustment for body mass index and other covariates, insulin in nondiabetic hypertensive individuals has weak negative relations to LV chamber size, mass, and stroke volume, and also has weak positive relations to relative wall thickness but not to measures of LV systolic function. Thus, native plasma insulin level may not play a major independent role in the pathogenesis of hypertensive LV hypertrophy or dysfunction.