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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with non-insulin-dependent diabetes mellitus, concentrations in plasma of insulin and its precursors, proinsulin and split proinsulin, are increased. Because increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) occur also, we hypothesized that proinsulin and split proinsulin may augment endothelial cell PAI-1 expression, thereby potentially attenuating endogenous fibrinolysis and accelerating atherosclerosis. Proinsulin increased PAI-1 activity in conditioned media of endothelial cells as did split proinsulin, paralleled by increased expression of PAI-1 mRNA. These effects of proinsulin were not dependent on its conversion to insulin nor on its interactions with the insulin receptor. The proinsulin stimulation of PAI-1 expression was not attenuated by either anti-insulin receptor antibodies or a 100-fold excess of insulin. Furthermore, proinsulin-mediated increases in PAI-1 expression were not inhibited by a 500-fold excess of insulinlike growth factor I. In addition, inhibition of tyrosine kinase, which mediates many of the diverse effects of insulin and insulinlike growth factor I, did not attenuate the effect of proinsulin. These results indicate that proinsulin augments PAI-1 expression, potentially contributing to vasculopathy in patients with non-insulin-dependent diabetes mellitus.
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PMID:Stimulation by proinsulin of expression of plasminogen activator inhibitor type-I in endothelial cells. 161 5

Three polymorphic sites of the apolipoprotein B gene - the insertion/deletion signal peptide, XbaI and EcoRI sites - were examined in a sample of 107 healthy men and in 46 men with evidence of coronary heart disease selected from a large population survey of South Asians aged 40-69 in London, U.K. There were no significant differences in allele frequencies between cases and controls. Frequencies of the ins (insertion) and X- (absence of XbaI cutting site) alleles were higher in South Asians than in Europeans studied previously (South Asians versus Europeans ins: 0.80 vs. 0.68, P less than 0.025; X-: 0.71 vs. 0.47-0.56, P less than 0.001). The del allele was associated with higher levels of total cholesterol (P less than 0.05) and the X+ allele with lower levels of HDL cholesterol (P less than 0.05), and thus both polymorphisms were associated with differences in the ratio of HDL cholesterol to total cholesterol (ins/del, P less than 0.01; XbaI, P less than 0.001). Mean waist-hip girth ratio was lower in the 10 men homozygous for the X+ allele than in the 42 men with X-/X+ and 55 men with X-/X- genotypes; the means (+/- SEM) were 0.92 +/- 0.02, 0.97 +/- 0.01 and 0.96 +/- 0.01 respectively (P = 0.03). These data suggest that genetic variation in linkage disequilibrium with the XbaI and ins/del polymorphisms of the apo B gene contributes to the determination of total cholesterol and HDL cholesterol levels and possibly to obesity in South Asians.
Atherosclerosis 1991 Dec
PMID:Apolipoprotein B gene polymorphisms are associated with lipid levels in men of South Asian descent. 178 9

We have studied low density lipoprotein (LDL) subclass distribution in a group of male patients with non-insulin-dependent diabetes mellitus (NIDDM) and investigated its relationships to fasting and postprandial triglyceride (TG)-rich lipoproteins, insulin resistance, lipoprotein lipase (EC 3.1.1.3; LPL), hepatic lipase (EC 3.1.1.34; HL), lecithin:cholesterol acyl transferase (EC 2.3.1.43; LCAT) and cholesteryl ester transfer protein (CETP) activities. LDL was subfractionated by density gradient ultracentrifugation. Postprandial lipoproteins were measured after an oral fat load using retinyl palmitate as a marker for intestinal TG-rich lipoproteins. Hypertriglyceridaemic NIDDMs (HTG) had a preponderance of small dense LDL particles present in the plasma and reduced amounts of large buoyant species when compared to normotriglyceridaemic patients (NTG) and controls. Both groups of diabetics were more insulin resistant than the controls (P < 0.05) and had raised concentrations of proinsulin (P < 0.05), although insulin content did not differ significantly. 32-33 split proinsulin (SPI) was the major insulin-like molecule present in HTG and was present in significantly higher amounts in these patients (P < 0.05) than either NTG or control subjects and correlated significantly with the presence of small dense LDL particles. After a test meal, the postprandial chylomicron response was greater in HTG than either NTG diabetics or controls (P < 0.05). Chylomicron remnants were present to a greater extent in HTG than in NTG and controls (P < 0.05), although in this case NTG also contained more chylomicron remnants than control subjects (P < 0.05). There was no difference in the LPL activity, CETP and LCAT between diabetics and controls, whereas an increase in hepatic lipase activity was seen in the HTG diabetics (P < 0.05). Both CETP and LCAT activities increased postprandially. Multivariate analysis showed that TG, HDL content and HL activity were the most important determinants of small dense LDL concentration in the fasting state (R2 = 67%). Postprandially, chylomicron remnant clearance, HL and insulin resistance were the major determinants (R2 = 61%) of LDL-III.
Atherosclerosis 1995 Mar
PMID:Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance. 760 66

Clinical hyperproinsulinemia occurs not only in familial hyperproinsulinemia, but also in insulinoma, renal failure, and even in non-insulin-dependent diabetes mellitus (NIDDM). The etiology of hyperproinsulinemia is divided into (1) abnormality of pro-insulin molecules, (2) abnormality of pancreatic beta-cells other than proinsulin molecules, (3) retardation of proinsulin clearance. Hyperproinsulinemia is now thought to be both a result of the above-mentioned diseases and a cause of atherosclerosis in patients with NIDDM. Recent developments in molecular biology have deepened our knowledge of the biosynthesis and role of proinsulin, especially the prohormone sorting mechanism into secretory granules in pancreatic beta-cells.
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PMID:[Etiology and molecular biology of hyperproinsulinemia]. 798 77

Recent large-scale epidemiological studies demonstrate that blood concentrations of immunoreactive insulin predict the development of NIDDM and IDDM and are associated with the risk of several degenerative diseases, such as coronary and peripheral vessel atherosclerosis, hypertension, and dyslipidemia. The reliability of these measurements is dependent on a biological assay that has not been well standardized between laboratories. Recognizing this, the American Diabetes Association organized a task force to assess comparability of blood insulin measurements between laboratories and to suggest techniques to improve comparability. The task force found that identical serum and plasma samples measured in different laboratories produced widely disparate values that were unacceptable for population comparisons. Use of a single reference standard did little to improve comparability. Assay characteristics such as linearity, recovery, accuracy, and cross-reactivity to proinsulin and its primary conversion intermediates varied among the laboratories, and they did not readily explain differences in the measurements made from assay to assay. Use of the same assay kit in different laboratories did not always ensure comparable measurements. Linear regression of assay results from one laboratory to an arbitrarily chosen reference assay greatly improved comparability and demonstrated the potential value in comparing each assay to a reference method. The task force report defines acceptable assay characteristics and proposes a three-step process of insulin assay proficiency and comparability. A central reference assay and ongoing sample exchange will be needed to allow reliable comparisons of insulin measurements made in different laboratories. Rigorous quality control and continuous quality improvement are needed to maintain reliability of the insulin measurement.
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PMID:Report of the American Diabetes Association's Task Force on standardization of the insulin assay. 854 70

Controversy persists about whether hyperinsulinemia and hyperproinsulinemia are independent risk markers for coronary atherosclerosis. A common limitation of most previous studies has been imprecise categorization of disease status in normal and coronary artery disease (CAD) groups. We assessed the relationship of pancreatic beta-cell secretory products and premature CAD in a case-control study of 134 nondiabetic subjects, aged < or = 55 years old, carefully defined for CAD status by catheterization and/or thallium stress studies. Case patients comprised 66 patients with premature CAD, and control subjects (non-CAD group) included 68 patients without CAD but with traditional CAD risk factors and chest pain and/or abnormal electrocardiograms but normal catheterization and/or thallium stress studies. In addition to the CAD and non-CAD group comparison, both groups were compared with a reference group of 27 mixed lean and obese control volunteers. All CAD and non-CAD patients had a 3-h 75-g oral glucose tolerance test with measurement of fasting and post-glucose load immunoreactive insulin (IRI), specific insulin (INS), proinsulin-like material (PI), and C-peptide. Increased fasting insulin and fasting proinsulin levels both were statistically significantly associated with higher odds of being in either the premature CAD and the non-CAD groups when compared with the reference group in a polychotomous logistic regression model (odds ratio of at least 1.20 for a 20% increase in each beta-cell secretory product in both comparisons, P < 0.05). However, increased pancreatic beta-cell secretory hormone levels did not show a statistically significant relative risk for being in the premature CAD group when compared with the non-CAD group. After adjustment for BMI, all statistically significant associations disappeared for IRI, INS, and PI when the odds favoring being in the CAD and non-CAD groups were compared versus the reference group. Furthermore, the odds of being in the premature CAD and non-CAD groups when compared with the reference group were not significantly associated to the ratio of PI to insulin and C-peptide. Thus, although there is a statistically significant association between the odds of having premature CAD with elevated insulin and proinsulin levels compared with the reference group, these findings are equally common in subjects with traditional CAD risk factors without detectable CAD. Furthermore, the association of higher insulin and proinsulin levels with the likelihood of a patient having or not having CAD disappears after adjustment for BMI, suggesting that insulin and proinsulin are not independent risk markers but are primarily dependent on obesity.
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PMID:Are insulin and proinsulin independent risk markers for premature coronary artery disease ? 863 46

We investigated the effects of apolipoprotein (apo) B signal peptide length polymorphisms on low density lipoprotein cholesterol (LDL-C), apo B, and post-challenge (2 h) glucose levels in 686 Mexican Americans from 34 families. The most common allele encoded an apo B signal peptide of 27 amino acids (ins; SP-27), the next most frequent allele encoded a 24 amino acid signal peptide (del; SP-24), and the rarest allele encoded a 29 amino acid signal peptide (ins; SP-29) that has been found only in Mexican Americans. Homozygotes for the SP-24 allele had significantly higher mean levels of apo B. LDL-C, and 2-h glucose than SP-27 homozygotes, and SP-27/SP-24 heterozygotes had intermediate levels (P = 0.01 for apo B, P < 0.001 for LDL-C, and P = 0.04 for 2-h glucose). Heterozygotes for the SP-29 allele had higher apo B and LDL-C levels compared to homozygotes for the SP-27 or SP-24 alleles. Apo B signal peptide length polymorphism accounted for 4.2%, 3.5%, and 3.0% of the residual variation in LDL-C, apo B, and 2-h glucose levels, respectively, among the Mexican American families.
Atherosclerosis 1996 Feb
PMID:Apolipoprotein B (apo B) signal peptide length polymorphisms are associated with apo B, low density lipoprotein cholesterol, and glucose levels in Mexican Americans. 864 69

There is interindividual variation in plasma lipid response to dietary changes. The polymorphisms which are associated with plasma lipid levels could possibly explain part of this variation. Therefore, the apolipoprotein B (apo B) signal peptide insertion/deletion (ins/del) and XbaI restriction fragment length polymorphisms are possible regulators of plasma lipid responses. We examined their role in the regulation of plasma lipid responses in 87 North Karelians (43 men, 44 women). The dietary study consisted of a 2-week baseline period (34-35% of energy from fat), followed by an 8-week low-fat (24 En%), low-cholesterol (279 mg/d) diet period and an 8-week switchback period. In this study population the apo B ins/del and XbaI polymorphisms exhibited mainly similar and partly significant effects on the responses of plasma very low-density lipoprotein (VLDL) and high density lipoprotein2 (HDL2) cholesterol to dietary changes. After consumption of the low saturated fat, low-cholesterol diet, ins/ins X - /X - homozygotes showed the greatest increase in VLDL cholesterol (p < 0.05 for differences between ins/del genotypes) and the greatest fall in HDL2 cholesterol (p = 0.01 for ins/del and p = 0.05 for XbaI), while only minimal alterations were seen in the del/del and X + /X + groups. After returning to the original diet, the changes of these lipids were reversed, ins/ins and X -/X - homozygotes having the greatest reductions in VLDL cholesterol (p < 0.05 for XbaI) and the greatest increases in HLDL2 cholesterol (p < 0.001 for XbaI). The findings suggest that plasma VLDL and HDL2 cholesterol responsiveness to diet may be partly explained by variation at the apo B gene.
Atherosclerosis 1996 Apr 26
PMID:The effects of the apolipoprotein B signal peptide (ins/del) and XbaI polymorphisms on plasma lipid responses to dietary change. 872 6

Elevated plasminogen activator inhibitor type 1 (PAI-1) activity has been shown to correlate with plasma insulin, proinsulin-like molecules, serum triglycerides and insulin sensitivity in both non-insulin dependent diabetic (NIDDM) subjects and subjects with coronary heart disease. We examined the relative roles of these variables in determining PAI-1 activity in four groups of male caucasian subjects: non-diabetic subjects with (n = 38) and without (n = 38) previous myocardial infarction (MI) and NIDDM subjects with (n = 26) and without (n = 30) previous MI. Insulin and proinsulin-like molecules were measured using specific two-site immunometric assays and insulin sensitivity estimated using the Homeostasis Model Assessment (HOMA) model. Subjects were comparable in age and body mass index. In univariate analysis, there were significant correlations of PAI-1 activity with intact and des-31,32-proinsulin and serum triglycerides in non-diabetic subjects with (r = 0.52, P = 0.001; r = 0.58, P < 0.001; r = 0.41, P = 0.010) and without (r = 0.31, P = 0.056; r = 0.46, P = 0.006; r = 0.41, P = 0.011) MI, but not with plasma insulin or insulin sensitivity. In NIDDM subjects, PAI-1 activity correlated significantly with intact and des-31,32-proinsulin and serum triglyceride (r = 0.47, P = 0.015; r = 0.58, P = 0.002; r = 0.44, P = 0.026) only in subjects with MI. In multiple regression analysis, MI was the most important determinant of PAI-1 activity levels (r2 = 0.31, F = 55.6, P < 0.001). In conclusion, concentrations of proinsulin-like molecules and serum triglycerides appear to be stronger determinants of PAI-1 activity than plasma insulin or insulin sensitivity in both NIDDM subjects and non-diabetic subjects with and without MI. However, the relationship of MI with PAI-1 activity is independent of these variables.
Atherosclerosis 1997 Apr
PMID:Proinsulin-like molecules and plasminogen activator inhibitor type 1 (PAI-1) activity in diabetic and non-diabetic subjects with and without myocardial infarction. 912 61

Elevated PAI-1 levels were described in different insulin resistant conditions, incl. diabetes mellitus type II. In its formation probably several stimulating factors participate. Hitherto accomplished studies suggest not only the important effect of insulin acting synergically with very low density. lipoproteins (VLDL) on hepatocytes but also the importance of the endothelial pool where the action of proinsulin, VLDL and cytokines in synergy with Cai-dependent stimuli (oxidation stress, thrombin) is involved. Under certain circumstances also another adipocyte compartment may play a role, and a significant role of thrombocytes in raising the PAI-1 level cannot be ruled out either. A more detailed analysis of the raised PAI-1 level in different patients could extend the possibilities of therapeutic reduction of levels of this important risk factor of atherosclerosis.
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PMID:[Plasminogen activator inhibitor (PAI-1) and diabetes mellitus. I. Regulation of PAI-1 levels]. 960 94


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