Characteristics of young offspring of type 2 diabetic parents in a biracial (black-white) community-based sample: the Bogalusa Heart Study.

The impact of race (black-white) and family history of type 2 diabetes mellitus on metabolic characteristics in early life was examined in a community-based sample from Bogalusa, LA. Study subjects included offspring of type 2 diabetics (n = 53, 47% black) and nondiabetics (n = 52, 40% black), with the mean age of each group ranging from 14.2 to 15.6 years. Offspring were given a 1-hour oral glucose tolerance test. Measures of body fatness such as body weight, body-mass index (BMI; weight/height2), and triceps and subscapular thicknesses were significantly higher only in white offspring of diabetics versus nondiabetics; measures of abdominal fat (waist circumference and waist-to-hip ratio) were significantly higher among offspring of diabetics of both races. Among the measures of glucose homeostasis, basal glucose, insulin, insulin-to-C-peptide ratio (a measure of hepatic insulin extraction), insulin resistance index (derived from basal glucose and insulin levels), and glucose response after glucose challenge were higher in the offspring of diabetics of both races. The differences in insulin-to-C-peptide ratio and glucose response remained significant after adjusting for BMI; further, these two variables were independently associated with parental diabetes in both races. Waist-to-hip ratio, glucose response, C-peptide response (a measure of insulin secretion) were lower, and basal insulin-to-C-peptide ratio and postglucose suppression of free fatty acids greater in blacks versus whites, regardless of status of parental diabetes. Black-white differences in postglucose suppression of free fatty acids disappeared after adjusting for BMI. Thus, blacks and whites with parental type 2 diabetes show multiple abnormalities in parameters governing glucose homeostasis early in life, and some of these traits differ between the races, regardless of status of parental diabetes.

Proteoglycans in human coronary arteriosclerotic lesions.

Proteoglycans in human coronary arteries were characterized immunohistochemically, using specific monoclonal antibodies to distinct proteoglycan types. In addition, apoB, macrophage, and arterial smooth muscle cell alpha-actin markers were localized. The expression of chondroitin sulfate proteoglycans and apoB was observed in healthy areas (operationally defined by morphology) as well as in lesions in the intima, but with greater expression in the atheromatous lesions. In healthy intima heparan sulfate proteoglycan was cell associated, but in lesions it was found also in the extracellular space. A dermatan sulfate proteoglycan of decorin type was not observed in the healthy intima but was observed in the intima with adaptive thickening especially in zones with reduced staining for smooth muscle cell alpha-actin. In atheroma (fibrous plaque with necrotic core) decorin along with alpha-actin and macrophage marker stained brightly in the extracellular regions in fibrous cap (actively progressing lesion) but was sparse in fibrous base (quiescent lesion). The observations suggest that decorin along with extracellular alpha-actin and macrophage marker may be useful for differentiating lesions that tend to progress with disease.

Plasma insulin-like growth factor 1 distribution and its relation to blood pressure in adolescents: the Bogalusa Heart Study.

The distribution of circulating insulin-like growth factor-1 (IGF-1) and its relationship to blood pressure was examined in a community study of 1073 biracial (black-white) adolescents aged 11 to 18 years. Girls of both races displayed higher levels of plasma IGF-1 than did their male counterparts (P < .01), independent of age and sexual maturation. In boys, IGF-1 was correlated positively with height (r = 0.37 P < .001), weight (r = 0.26, P < .001), Tanner stage (r = 0.31, P < .001), and age (r = 0.11, P < .05). Girls, on the other hand, showed an inverse association with age (r = -0.38, P < .001) and Tanner stage (r = -0.10, P < .05). Plasma IGF-1 was correlated positively with systolic blood pressure in boys of both races (r = 0.21 to 0.25, P < .01) and with diastolic blood pressure in white boys (r = 0.18, P < .05), but not in girls of either race. Boys with elevated levels of IGF-1 (>80th percentile) showed significantly higher blood pressure levels, especially during early to middle stages of puberty. Multivariate analysis revealed that IGF-1 was associated with systolic and diastolic blood pressure, independent of age, race, sexual maturation, height, weight, and insulin in boys. These results suggest that plasma IGF-1 may contribute to the regulation of blood pressure only in males during puberty.

Racial (black-white) differences in insulin secretion and clearance in adolescents: the Bogalusa heart study.

OBJECTIVE: Earlier we found black-white contrast in insulin levels in adolescents. The purpose of this study is to assess whether this difference is attributable to alterations in insulin secretion and/or clearance. METHODS: Fasting circulating insulin and C-peptide concentrations were examined in 1157 adolescents aged 11 to 18 years from a biracial community. Fasting plasma C-peptide, C-peptide to insulin ratio, and glucose to insulin ratio were used as indices of insulin secretion, hepatic insulin clearance, and insulin sensitivity, respectively. RESULTS: After adjusting several covariates (age, sexual maturation, and obesity), black adolescents had higher insulin levels (14.99 vs 12.66 microU/mL in girls). However, they had lower C-peptide levels than their white counterparts, indicating lower insulin secretion by pancreatic beta cells in black adolescents. Moreover, black adolescents had lower levels of C-peptide to insulin ratio than white adolescents (0.14 vs 0.17), suggesting reduced hepatic insulin clearance in black adolescents. In addition, significantly lower levels of glucose to insulin ratio in black girls suggest a reduced insulin sensitivity in this group. Further, differences in insulin levels between white and black girls disappeared after adjusting for differences in C-peptide to insulin ratio. CONCLUSION: These data suggest that elevated insulin levels observed in black adolescents, especially in black girls, may be attributed to their decreased hepatic insulin clearance, not hypersecretion of insulin.

Microalbuminuria in young adults related to blood pressure in a biracial (black-white) population. The Bogalusa Heart Study.

The association between microalbuminuria and blood pressure levels was examined in young white and black adults (n = 1131) aged 19 to 32 years. Urinary ratio of albumin (mg/L) to creatinine (mmol/L) was used as an estimation of urinary albumin excretion. Black men and women compared with their white counterparts had higher levels of blood pressure. Significantly positive correlations between urinary albumin excretion and systolic and diastolic blood pressures were observed in black men (r = 0.20 and r = 0.24, P < .01) and black women (r = 0.15 and r = 0.14, P < .05). Similar correlations of significance were not seen in the white counterparts. Systolic and diastolic blood pressure levels were significantly higher in normotensive black subjects (< 140/90 mm Hg) with increased urinary albumin excretion (> or = 90th percentile) than in those without increased urinary albumin excretion. After accounting for potential confounding by age, sex, and body mass index, blacks in the uppermost systolic and diastolic blood pressure group were 7.1 times (95% CI, 2.0 to 25.8) and 4.8 times (1.3 to 18.3), respectively, as likely to have elevated albumin/creatinine excretion as those in the lowest group. In contrast, the likelihood for elevated albumin/creatinine excretion were 0.9 times (95% CI, 0.5 to 2.2) and 1.1 times (0.5 to 2.3), respectively, in whites, which were not significant. These data suggest that a stronger association between blood pressure levels and urinary albumin excretion exists in young blacks than in whites, which supports the notion that blacks may be more susceptible to renal damage from relatively low levels of blood pressure increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Normative distribution of complete blood count from early childhood through adolescence: the Bogalusa Heart Study.

BACKGROUND: Noting the distribution of blood values in a biracial southern community according to age, sex, and race variations will help in understanding the normative developmental changes in early life and provides background information. METHODS: Complete blood counts were obtained from 3,018 free-living children ages 5-17 years from a well-defined black-white community as part of a cardiovascular risk factor screening. RESULTS: For children ages 5-17 years, hemoglobin levels, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and red blood count increased (P < 0.01) with age. Levels of platelet count and white blood count decreased (P < 0.0005) with age. Compared with females, males between ages 12 and 17 years have (P < 0.05) 0.4 x 10(12)/liter higher red blood count, 1 g/dl higher hemoglobin, 2% higher hematocrit, 0.2 g/dl higher mean corpuscular hemoglobin concentration, 0.5 x 10(9)/liter lower white blood count, 1.4 fl lower mean corpuscular volume, 0.3 pg lower mean corpuscular hemoglobin, and 14 x 10(9)/liter lower platelet count. Compared with blacks, whites have (P < 0.05) 0.5 10(9)/liter higher white blood count, 0.05 10(12)/liter higher red blood count, 0.7 g/dl higher hemoglobin, 1.7% higher hematocrit, 2.4 fl higher mean corpuscular volume, 1 pg higher mean corpuscular hemoglobin, and 0.5 g/dl higher mean corpuscular hemoglobin concentration. A positive association was noted among blood count variables and hemoglobin with blood pressure similar to that in adults. CONCLUSION: Blood values differ by age, sex, and race. These differences change at maturation and should be considered when defining normal and "abnormal" blood values.

Lipoprotein-proteoglycan complexes induce continued cholesteryl ester accumulation in foam cells from rabbit atherosclerotic lesions.

We studied the metabolism of lipoprotein-proteoglycan complexes by macrophage-derived foam cells. Foam cells were isolated from atherosclerotic rabbit aortas. ApoB-lipoprotein-proteoglycan complex was isolated from human aorta fibrous plaque lesions and LDL-proteoglycan complex was formed in vitro. Both in vitro and in vivo complexes stimulated cholesteryl ester synthesis in foam cells by a dose-dependent, saturable process that resulted in the intracellular accumulation of cholesteryl ester. Stimulation of cholesteryl ester synthesis was linear with time over a 32-h period. Polyinosinic acid inhibited the stimulation of cholesteryl ester synthesis by the complexes by 32-37%, whereas cytochalasin D only produced a 6-16% inhibition. Foam cells degraded 125I-LDL-proteoglycan complex and 125I-acetyl LDL in a saturable, dose-dependent manner. Excess unlabeled acetyl-LDL inhibited the degradation of 125I-LDL-proteoglycan complex by 52%, while LDL had no effect. Similarly, excess unlabeled complex suppressed the degradation of 125I-acetyl-LDL by 48%. Foam cells degraded 125I-methyl-LDL-proteoglycan complex to the same extent as 125I-LDL-proteoglycan complex. These results show that foam cells from atherosclerotic lesions metabolize lipoprotein-proteoglycan complexes predominantly via receptor-mediated endocytosis and consequently continue to accumulate intracellular cholesteryl ester.

Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (The Bogalusa Heart Study).

Race and sex differences in aorta and coronary atherosclerotic lesions were studied in 150 persons aged 6 to 30 years. The intimal surface involvement with aorta fatty streaks was extensive, 0 to 71%, and greater in blacks than in whites (32 vs 20%, p less than 0.001). Coronary artery fatty streaks were more extensive in male than in female subjects (range 0 to 22%). Fibrous plaque lesions were present but not extensive in either the aorta (0 to 12%) or the coronary artery (0 to 24%) specimens. Lesions were more prevalent in male than in female persons, particularly white male subjects. The relation of fatty streaks to fibrous plaques was greater in the coronary vessels than in the aorta. In male subjects, aorta fatty streaks were strongly related to antemortem levels of total cholesterol, low-density lipoprotein cholesterol and ponderal index in white male subjects. Coronary artery fatty streaks in white male persons were significantly associated with serum triglycerides, very low density lipoprotein cholesterol, systolic and diastolic blood pressure and ponderal index. These results link antemortem risk factors to the development of atherosclerotic lesions and emphasize the need for preventive cardiology in early life.

Variations in the composition of arterial wall isomeric chondroitin sulfate proteoglycans among different animal species.

1. Isomeric chondroitin sulfate proteoglycans were extracted from human, bovine, swine and rabbit aortas by 4 M guanidine-HCl and were fractionated and purified by CsCl isopycnic centrifugation, Sepharose CL-4B gel filtration, DEAE-Sepharose ion-exchange chromatography and octyl-Sepharose hydrophobic interaction chromatography. 2. The molecular size and the composition of isomeric chondroitin sulfate proteoglycans varied among species. Variations were also noted in the composition and molecular weight of constituent glycosaminoglycan chains. 3. Observations made on chondroitinase ABC and chondroitinase AC digests of proteoglycans indicate that dermatan sulfate is linked to the core proteins through chondroitin sulfates.

Composition of proteoglycans in the aortas of copper-deficient rats.

Copper deficiency adversely affects the extracellular matrix of the arterial wall, leading to cardiovascular lesions. To study the lesions resulting from copper deficiency, the composition of proteoglycans from aortas of copper-deficient rats was compared with proteoglycans of aortas from copper-supplemented rats. Copper deficiency in rats was verified by copper levels in adrenal glands (mean +/- SE, 0.37 +/- 0.07 vs 1.03 +/- 0.17 micrograms/g wet wt in supplemented rats). The proteoglycans were isolated from the aorta by extraction with 4 M guanidine-HCl and by digestion of the tissue with elastase. The proteoglycans were purified by CsCl isopycnic centrifugation and fractionated by gel filtration. The fractions were characterized for molecular size and glycosaminoglycan composition. Total uronate in the aortas from copper-deficient rats was 25% greater than in aortas from copper-supplemented rats, and the proteoglycans from copper-deficient rat aortas were of greater molecular size. Among the glycosaminoglycans the concentration (microgram/mg tissue) of isomeric chondroitin sulfates, particularly dermatan sulfate, was greater in copper-deficient animals than in copper-supplemented animals. These observations are similar to earlier findings in experimental atherosclerosis and to a response of cardiovascular connective tissue to injury.

Effect of low-density lipoproteins on the synthesis and secretion of proteoglycans by human endothelial cells in culture.

We studied the effect of low-density lipoproteins (LDL) on the synthesis and secretion of proteoglycans by cultured human umbilical-vein endothelial cells. Confluent cultures were incubated with [35S]sulphate or [3H]glucosamine in lipoprotein-deficient serum in the presence and in the absence (control) of LDL (100-400 micrograms/ml), and metabolically labelled proteoglycans in culture medium and cell layer were analysed. LDL increased accumulation of labelled proteoglycans in medium and cell fractions up to a concentration of 200 micrograms/ml. At this concentration of LDL the accumulations of proteoglycans in medium and cell layer were 65% and 32% respectively above control for 35S-labelled proteoglycans, and 55% and 28% respectively above control for 3H-labelled proteoglycans. At concentrations above this LDL was found to depress the accumulation of proteoglycans in medium and cell layer. Gel filtration on Sepharose CL-4B showed that in both control and LDL-treated cultures the cell layer contained a large (Kav. = 0) and a small (Kav. = 0.35) heparan sulphate proteoglycan, whereas the culture medium contained a large heparan sulphate proteoglycan (Kav. = 0) and a smaller isomeric chondroitin sulphate proteoglycan (control, Kav. = 0.35; LDL-treated, Kav. = 0.17). The relative increase in hydrodynamic size of the isomeric chondroitin sulphate proteoglycan (Mr 150,000 compared with 90,000) in the medium of cultures exposed to LDL was partly attributable to the larger size of the glycosaminoglycan side chains (Mr 39,000 compared with 21,000). The isomeric chondroitin sulphate proteoglycan in LDL-treated culture was relatively enriched in chondroitin 6-sulphate compared with that in control cultures (39% compared with 29%). Pulse-chase studies showed that LDL treatment did not alter the turnover rate of proteoglycans as compared with controls, implying that the elevation in proteoglycan accumulation in LDL-treated cultures was due to enhanced synthesis. These results demonstrate that LDL can modulate proteoglycan synthesis by cultured vascular endothelial cells, resulting in the secretion of a larger isomeric chondroitin sulphate proteoglycan enriched in chondroitin 6-sulphate.

Arterial wall injury and proteoglycan changes in atherosclerosis.

The concept of injury as a mechanism leading to atherosclerosis has been fostered by numerous studies of initiating factors and by observation of the response of cardiovascular connective tissue, ie, cellular and extracellular matrix components. Carbohydrate-protein macromolecules of the extracellular matrix are a complex group of biologically important substances that play a crucial role in mesenchymal tissue repair following injury, a process needed to maintain arterial wall integrity. Of particular interest are the proteoglycans that enter into a variety of roles, from that of inhibiting atherosclerosis and helping to maintain fibrillar structures to that of taking part in lipid deposition in the development of atherosclerosis.

Use of 86Rb and 22Na in assaying active and cotransport activities in human erythrocytes in a biracial population.

A defect in Na+-K+ transport across the red cell membrane has been shown to be associated with essential hypertension. A sensitive assay system to measure active, co- and countertransport systems in erythrocytes from normotensive adults was developed. Active, co- and countertransport systems in the erythrocytes were assayed by measuring the influx of radioactive 22Na+ and 86Rb+. In the biracial (black-white) population group studied, analysis of variance of the active transport showed a significant race effect (p = 0.003). Cotransport activity showed age by race interaction (p = 0.001) and age by sex (p = 0.02). Cotransport activity was significantly higher in whites than blacks (p = 0.0001). Countertransport activity did not vary either by sex or race. Of the Spearman correlation coefficients for transport activities and blood pressure, white males showed a strong positive correlation with countertransport, whereas in black males, blood pressures showed a strong interaction with active transport. Among the transport activities, active transport showed significant interaction with countertransport activity in black males, whereas cotransport activity in whites showed a strong interaction with countertransport. The results suggest a subtle difference in Na+-K+ transport systems between blacks and whites, and these variations may be related to differences for susceptibility to essential hypertension.

Low density lipoprotein binding affinity of arterial wall isomeric chondroitin sulfate proteoglycans.

Although the selective interaction of low density lipoproteins (LDL) with arterial proteoglycans is known, information is lacking on LDL-binding affinity of different subspecies occurring within a proteoglycan family. Isomeric chondroitin sulfate proteoglycan preparations sedimenting at densities of 1.54 g/ml (D1), 1.50 g/ml (D2) and 1.46 g/ml (D3) were isolated from bovine aorta intima-media under dissociative conditions and subjected to equilibrium binding to LDL-agarose gel. D1, D2 and D3 contained 36%, 37% and 11% dermatan sulfate, respectively. Sulfate to hexosamine ratio was low (0.73) in D1 when compared to D2 and D3 (0.94 and 1.04). Of the total proteoglycans contained in D1, D2 and D3, 41%, 52% and 66% interacted with LDL, respectively. LDL-bound proteoglycans dissociated over a wide range of ionic strengths (0.15-1.0); in comparison, LDL-bound heparin dissociated within a narrow range (0.5-0.75). Unlike other preparations, 30% of bound D3 dissociated at an ionic strength of 1.0. In D1 and D2 the proportion of dermatan sulfate increased in proteoglycan fractions that were bound firmly to LDL, whereas a high affinity fraction in D3 contained no dermatan sulfate. Thus, isomeric chondroitin sulfate proteoglycans display considerable divergence with respect to LDL binding. This may depend not only on the degree of sulfation but on other characteristics of the chondroitin sulfate isomers as well.

Composition of proteoglycans synthesized by rabbit aortic explants in culture and the effect of experimental atherosclerosis.

The synthesis of proteoglycans by aorta explants from rabbits with diet-induced atherosclerosis and controls was studied by 35S-incorporation. Proteoglycans were isolated under dissociative conditions from incubation medium and from arterial explants. Additionally, the tissue proteoglycans that were not extracted by 4 M guanidine-HCl were solubilized by digestion of the tissue by elastase in the presence of proteinase inhibitors. The residual tissue was hydrolyzed by papain and glycosaminoglycans were isolated. The atherosclerotic aorta tissue incorporated twice the amount of 35S into proteoglycans than observed for controls; in both groups about 70% of the label incorporated into the tissue was noted in the proteoglycans extracted by guanidine-HC;, while about 30% of the total 35S-labeled proteoglycans synthesized by the explants were found in the media. Atherosclerotic tissue incorporated 35S predominantly into chondroitin sulfate proteoglycans when compared to control tissue. The chondroitinase ABC-digestable proteoglycans that were extracted by guanidine-HCl from atherosclerotic tissues were of larger molecular size than those from control tissue, but the core proteins from these preparations were similar. The heparan sulfate proteoglycan that was obtained by dissociative extraction from atherosclerotic tissue had greater amounts of N-acetyl and lesser amounts of N-sulfate ester groups than the preparation from control tissue. Digestion of the tissue by elastase yielded heparan sulfate proteoglycan as the major constituent in both groups, although atherosclerotic tissue contained relatively small amounts of this proteoglycan. The residual tissue from both groups contained chondroitin sulfate and heparan sulfate as the major glycosaminoglycans with the latter showing a decrease with atherosclerosis. Atherosclerotic tissue secreted into the medium about two-fold more 35S-labeled proteoglycans with larger molecular size than control tissue; proteoglycans of the heparan sulfate and chondroitin sulfate types were the major constituents in the culture medium of both tissues. Thus, proteoglycans undergo both quantitative and qualitative changes in atherosclerosis, reflecting the enhanced smooth muscle cell activity. These changes are potentially important in modulating lipoprotein binding and hemostatic properties, as well as fibrillogenesis of the arterial wall.

Composition of proteoglycans from human atherosclerotic lesions.

Proteoglycans from human atherosclerotic lesions and from uninvolved aortic intima were isolated and their composition was studied. The tissues were sequentially extracted by guanidine hydrochloride followed by hydrolysis of the tissue by elastase. Chondroitin sulfate/dermatan sulfate proteoglycans were predominant in guanidine hydrochloride extracts of the tissue. Most of the heparan sulfate proteoglycans were released from the tissue by hydrolysis with elastase. The content of proteoglycan material, measured as uronate per unit weight of wet tissue, was lower in fatty streaks and fibrous plaques than in uninvolved tissue (0.58 and 0.48 mg vs. 0.7 mg/g wet tissue). The distribution of different glycosaminoglycans in guanidine hydrochloride-extracted proteoglycans was similar among the lesions and uninvolved tissue, but varied in the elastase-hydrolyzed extracts. Gel filtration studies suggested that the major proteoglycan material, chondroitin sulfate proteoglycans, from lesions had greater molecular weight than proteoglycans from uninvolved tissue. The studies indicate that alteration in intrinsic composition and molecular size of proteoglycans occurs in atherosclerotic lesions.

Atherosclerosis and its evolution in childhood.

Cardiovascular risk factors in childhood are related to arterial wall changes that lead to atherosclerotic coronary artery disease in later life. Atherosclerosis begins early in life. The observations of early arterial wall connective tissue changes and accompanying early lipid deposition show the importance of understanding cardiovascular risk factors in children. Since risk factors found in childhood are potentially predictive of adult coronary heart disease, methods for prevention of atherosclerosis should begin in children. Rational strategies should be directed to removing atherogenic forces that work in a child at high risk. Primary prevention of atherosclerosis has its maximal potential when begun before advanced irreversible lesions can occur. Consideration needs to be directed to how cardiovascular connective tissue changes and lipid and calcium deposition can be modulated in the injury and healing processes. It is important to recognize that adult coronary artery disease is really a major pediatric problem.

Hepatic glycoprotein synthesis in streptozotocin diabetic rats.

In vitro incorporation of 3H-mannose into dolichol phosphate mannose, dolichol pyrophosphate oligosaccharides, and secretory and membrane glycoproteins was investigated in liver slices from streptozotocin diabetic rats. In addition, 14C-leucine incorporation into glycoproteins was studied. 3H-mannose incorporation was significantly less in secretory glycoproteins from diabetic rat liver slices than from control tissues, but 14C-leucine incorporation in these proteins was similar in both groups. Dolichol-phosphate mannose and dolichol-phosphate oligosaccharide synthesis were significantly down-regulated in diabetes. When incubated with insulin, mannosylation of secretory proteins, dolichol-phosphate mannose and dolichol-phosphate oligosaccharides reached control levels in three hours. Dolichol-phosphate mannosyltransferase activity was significantly less in diabetes, while in the presence of insulin, the enzyme activity reached control levels in three hours. These results indicate that key intermediates in glycoprotein biosynthesis are regulated by insulin.

Dolichol synthesis in liver slices of streptozotocin diabetic rats.

The rate of dolichol synthesis in normal and diabetic liver slices in the presence or absence of insulin was investigated with radiolabeled acetate and mevalonate as substrates. Cholesterol and dolichol syntheses were found low in diabetic rat liver slices when incubated either with 1-14C-acetate or 2-3H-mevalonate. In the presence of insulin, cholesterol and dolichol synthesis in diabetic rat liver slices returned to normal in nine hours when incubated with 1-14C-acetate; however, with 2-3H-mevalonate, synthesis of cholesterol and dolichol normalized in about three hours. These studies show that dolichol synthesis in rat liver slices is dependent on insulin.