Fasting hyperinsulinemia and cardiovascular disease risk factors in nondiabetic adults: stronger associations in lean versus obese subjects. Atherosclerosis Risk in Communities Study Investigators

The association between hyperinsulinemia and atherogenic risk factors has not been well studied in blacks and may be different for obese versus lean individuals. To investigate this possibility and to confirm the associations of hyperinsulinemia with cardiovascular disease risk factors in blacks and whites, we analyzed the joint associations of fasting serum insulin and obesity with risk factors in the Atherosclerosis Risk in Communities (ARIC) Study (1,293 black men, 4,797 white men, 2,033 black women, and 5,445 white women). Insulin values > or = 90th percentile (> or = 21 microU/mL) constituted hyperinsulinemia; body mass index (BMI) values > or = 27.3 kg/m2 for women and > or = 27.8 for men constituted obesity. Participants with hyperinsulinemia in all four race-sex groups had more atherogenic levels of most risk factors studied than those with normoinsulinemia. Among black men and women, mean levels of triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo) B, glucose, and fibrinogen (men only) were higher in hyperinsulinemic lean participants as compared with the normoinsulinemic obese group. Furthermore, most associations between insulin level and risk factors were stronger among lean versus obese subjects. For example, among lean black men, the difference in mean triglyceride concentration between those with hyperinsulinemia and those with normoinsulinemia was 147 - 99 = 48 mg/dL; among obese black men, the difference was 155 - 121 = 34 mg/dL (P < .05 for the interaction). Generally, similar negative interactions between BMI and insulin concentration were also observed among whites.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group

OBJECTIVE: The constellation of anomalies associated with insulin resistance is a plausible additional cause of ischemic cardiovascular disease and of NIDDM. To test this hypothesis in a primary prevention trial, the effects of metformin as a potential candidate for intervention in the insulin resistance syndrome (IRS) were evaluated in 324 middle-aged subjects with upper-body obesity. RESEARCH DESIGN AND METHODS: Trial patients were selected on the basis of a high waist-to-hip ratio. They were randomly allocated to receive either metformin or placebo, following a double-blind procedure. After 1 year of treatment, the main clinical and biological parameters of the IRS were assessed and their evolution compared between treatment groups. RESULTS: Compared with placebo, metformin induced a significant weight loss, a better maintenance of fasting blood glucose, total and LDL cholesterol levels, and a greater decrease of fasting plasma insulin concentration. Moreover, tissue-type plasminogen activator antigen, a marker of fibrinolytic impairment, showed a significant decrease under metformin. By contrast, metformin treatment had no significant effect on blood pressure or serum triglyceride and HDL cholesterol concentrations. The main side effect of metformin was diarrhea. CONCLUSIONS: The BIGuanides and Prevention of Risks in Obesity (BIGPRO1) results suggest that metformin would be a suitable candidate for long-term intervention for the prevention of diabetes but that its use in a trial of primary prevention of cardiovascular diseases requires either a reevaluation of its properties toward the most potentially atherogenic anomalies of the IRS or a better definition of the target population.     

Effect of desmopressin on plasma factor VIII and von Willebrand factor concentrations in Greyhounds

OBJECTIVE: To determine the effect of 1-Deamino-8-D-arginine vasopressin on plasma concentrations of von Willebrand factor and factor VIII in Greyhound blood donors, and to compare the response of 1-Deamino-8-D-arginine vasopressin injection on plasma concentrations of von Willebrand factor between groups with different resting plasma concentrations of von Willebrand factor. ANIMALS: Fifteen Greyhound blood donors were used. Dogs were grouped into three categories depending on their von Willebrand factor concentrations. PROCEDURE: Desmopressin was administered subcutaneously at 1 microgram/kg [corrected] to all dogs. Plasma von Willebrand factor and factor VIII concentrations were measured before and 10, 20, 30, 45, 60, 90 and 120 min after desmopressin injection. RESULTS: The von Willebrand factor and factor VIII concentrations in all dogs increased significantly and remained higher than base-line throughout the 2 h period. CONCLUSION: Desmopressin is useful in increasing von Willebrand factor concentrations in Greyhound blood donors, including those with low resting concentrations.     

Effect of parent weight on weight loss in obese children.

Assessed the effect of parent weight (obese/nonobese parent) and parent control vs child self-control on the weight loss of 41 obese 8–12 yr olds over a 3-yr period. Children of nonobese parents had significantly greater decrease in relative weight after 1 yr, but not after 3 yrs, than children of obese parents. Locus of control was not related to treatment outcome over the 3 yrs. Results suggest that parent weight was related to weight loss, but not weight maintenance, in obese children. (9 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor

No defects have been reported in moderately severe type 1 von Willebrand disease (vWD) with a clear autosomal dominant inheritance pattern, and the mechanism underlying this form of vWD remains obscure. We have studied a type 1 vWD family with such a dominant phenotype. The entire coding sequence of the von Willebrand factor (vWF) gene was analyzed by direct sequencing of DNA fragments amplified by polymerase chain reaction. Only one candidate mutation T(3445)-->C in exon 26 was detected that predicts a replacement of cysteine (C) at position 386 of the mature vWF subunit by arginine (R). Both mutant and normal vWF alleles were expressed as shown by analysis of platelet mRNA. This substitution segregates with vWD in the family and was not found in 100 unrelated individuals. The recombinant mutant vWF(C386R) was characterized by expression in 293T cells. The secretion of vWF(C386R) was greatly impaired due to retention in the endoplasmic reticulum. In cotransfections of normal and mutant vWF constructs, the vWF(C386R) subunits caused a dose-dependent decrease in the secretion of vWF. The multimer pattern remained nearly normal and consistent with a dominant vWD type 1 phenotype. The importance of the cysteine residues in the D3 domain of vWF in the pathogenesis of dominant type 1 vWD was further shown by the detection of another cysteine mutation, Cys367-->Phe, in two additional unrelated patients with a similar dominant type 1 vWD phenotype. We conclude that the loss of cysteine pairing in the D3 domain, leaving one free cysteine, can induce a purely quantitative deficiency of vWF by dominantly suppressing the secretion of normal vWF.     

Effects of decreasing sedentary behavior and increasing activity on weight change in obese children.

Obese children 8–12 years old from 61 families were randomized to treatment groups that targeted increased exercise, decreased sedentary behaviors, or both (combined group) to test the influence of reinforcing children to be more active or less sedentary on child weight change. Significant decreases in percentage overweight were observed after 4 months between the sedentary and the exercise groups (–29.9 vs. –23.2). At 1 year, the sedentary group had a greater decrease in percentage overweight than did the combined and the exercise groups (–28.7 vs. –20.3 and –8.7) and greater decrease in percentage of body fat (–4.7 vs. –2.3). All groups improved fitness during treatment and follow-up. Children in the sedentary group increased their liking for high-intensity activity and reported lower caloric intake than did children in the exercise group. These results support the goal of reducing time spent in sedentary activities to improve weight loss. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of external cues on the thinking behavior of obese and normal subjects.

Hypothesized that the thinking behavior of obese Ss is externally controlled to a greater extent than that of normals. 36 normal weight and 36 obese male undergraduates served as Ss. It was predicted that obese Ss would spend more time than normals thinking about an assigned topic of thought if there were topic-relevant external cues available, and less time than normals if there were no topic-relevant external cues available. With thinking measured directly by self-report and indirectly by distraction from pain, these predictions were confirmed. It is concluded that differences in eating behavior between obese and normal Ss can be explained by differences in thinking behavior. Therapeutic implications of the cognitive style of the obese are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increase by tri-iodothyronine of endothelin-1, fibronectin and von Willebrand factor in cultured endothelial cells

Hyperthyroidism is associated with elevated plasma levels of endothelium-derived proteins such as von Willebrand factor (vWF), fibronectin (FN) and endothelin-1 (ET-1). This study was designed to characterize the mechanisms involved in this phenomenon at the cellular level. vWF, FN and ET-1 secretion and mRNA expression were measured in human umbilical vein endothelial cells (HUVECs) exposed to tri-iodothyronine (T3) for 13 +/- 1 days, using ELISA, Western blot, RIA and Northern blot analysis respectively. Exposure of HUVECs to T3 significantly increased vWF secretion (50 ng T3/ml: 117 +/- 5%, P < 0.01; 100 ng T3/ml: 127 +/- 26%, P < 0.01) as well as vWF mRNA expression (50 ng/ml: 116 +/- 13%, P < 0.001; 100 ng/ml: 136 +/- 30%, P < 0.002) (results are means +/- S.D. analysed by the Wilcoxon signed rank test). FN secretion was significantly affected by 50 (145 +/- 42% of control, P < 0.05) and 100 (116.8 +/- 16% of control, P < 0.05) ng T3/ml, and FN mRNA expression by 50 ng T3/ml (123 +/- 20%, P < 0.05). Long-term incubation with T3 increased both ET-1 secretion (25 ng/ml: 124 +/- 25%, P < 0.001; 50 ng/ml: 165 +/- 53%, P < 0.05; 100 ng/ml: 116 +/- 17%, P < 0.05) and prepro-ET-1 mRNA expression (25 ng/ml: 112 +/- 16%, P < 0.05; 50 ng/ml: 134 +/- 43%, P < 0.02; 100 ng/ml: 120 +/- 20%, P < 0.02). Protein kinase C (PKC) isoforms epsilon and beta II were not significantly affected by T3, whereas PKC alpha was increased in whole cell lysates and in membrane fractions of cells incubated with 100 but not 50 ng T3/ml. Prepro-ET-1 mRNA stability, cell numbers and proliferation, measured by [3H]thymidine assays, remained unaffected in HUVECs after exposure to T3. These data indicate thyroid hormone-induced upregulation of mRNA expression and protein synthesis of vWF, FN and ET-1, by PKC alpha-, beta II- and epsilon-independent pathways, explaining, at least in part, increased plasma concentrations of endothelial proteins and peptides in the hyperthyroid state.     

Conformational changes in the A1 domain of von Willebrand factor modulating the interaction with platelet glycoprotein Ibalpha

The interaction between von Willebrand factor (vWF) A1 domain and platelet glycoprotein Ib alpha occurs in the presence of high shear stress or when vWF becomes immobilized onto a surface but not appreciably in the normal circulation. To investigate the structural properties regulating A1 domain function, we have used recombinant fragments prepared either in cyclic form with oxidized Cys509-Cys695 disulfide bond or reduced and alkylated. Interaction with glycoprotein Ibalpha was assessed by testing inhibition of monoclonal antibody LJ-Ib1 binding to platelets and inhibition of shear-induced platelet aggregation mediated by native vWF. Fragments exposed to pH between 2.5 and 3.5 adopted the molten globule conformation with loosened tertiary structure intermediate between native and completely unordered state. Maximal receptor binding activity was observed when fragments kept at acidic pH, particularly after reduction of the Cys509-Cys695 disulfide bond, were subjected to quick refolding by rapid pH increase. In contrast, slow refolding by incremental pH change over several hours resulted in at least 20-fold lower activity. A specific single point mutation (I546V) resulted in enhanced receptor binding, whereas another mutation (S561G) caused markedly reduced binding. These results provide experimental evidence that conformational transitions can modulate function of the vWF A1 domain in solution.     

Body weight change and carotid artery wall thickness. The Atherosclerosis Risk in Communities (ARIC) Study

The impact of weight change in adulthood on cardiovascular disease is controversial. This study examined the association of change in body weight, from young adulthood to middle age, with average carotid artery intimal-medial wall thickness by B-mode ultrasound measured in middle age. Participants were 13,282 men and women aged 45-64 years from the baseline examination of the Atherosclerosis Risk in Communities (ARIC) Study (1987-1989). Weight change was calculated as the difference between weight at the baseline examination and self-reported weight at age 25. White men gained a mean of 9.7 kg; black men, 10.1 kg; white women, 12.0 kg; and black women, 20.8 kg. Weight change was positively, albeit modestly, associated with intimal-medial thickness in black men and white men and in white women, but not in black women. Adjusted for age, examination center, smoking, education, sports activity level, height, and body mass index at age 25, the differences in intimal-medial thickness associated with a 10-kg increment in weight change were 0.016 (95% confidence interval 0.010 to 0.022) mm in white men, 0.008 (95% confidence interval 0.001 to 0.015) mm in black men, 0.013 (95% confidence interval 0.009 to 0.017) mm in white women, and 0.002 (95% confidence interval -0.002 to 0.006) mm in black women. These findings support the hypothesis that weight gain in adulthood promotes atherosclerotic changes in white men and women and in black men.     

Effects of cue salience on the behavior of obese and normal subjects.

Hypothesized that a Body Weight * Cue Salience interaction would occur in determining responsiveness to external cues. Ss were 37 normal and 33 obese male high school students. Obese Ss were expected to be more responsive than normal Ss to highly salient external cues and less responsive to low salient cues. Salience was manipulated by varying the loudness of an auditory cue. Results support the hypothesis (p     

Psychological and Behavioral Risk Factors for Obesity Onset in Adolescent Girls: A Prospective Study.

Because little is known about risk factors for obesity, the authors tested whether certain psychological and behavioral variables predicted future onset of obesity. The authors used data from a prospective study of 496 adolescent girls who completed a baseline assessment at age 11-15 years and 4 annual follow-ups. Self-reported dietary restraint, radical weight-control behaviors, depressive symptoms, and perceived parental obesity--but not high-fat food consumption, binge eating, or exercise frequency-predicted obesity onset. Results provide support for certain etiologic theories of obesity, including the affect regulation model. The fact that self-reported, weight-control behaviors identified girls at risk for obesity implies that high-risk youths are not engaging in effective weight-control methods and suggests the need to promote more effective strategies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of von Willebrand factor and fibrinogen in the initiation of platelet adhesion to thrombogenic surfaces

Platelets respond rapidly to alterations of endothelial cells by attaching firmly to the site of lesion, where exposure of subendothelial components may have occurred. The first layer of platelets is in contact with the thrombogenic surface (adhesion), whereas subsequent growth of the hemostatic plug depends on platelet-to-platelet interactions (aggregation). Both aspects of platelet function are influenced by von Willebrand factor and fibrinogen interaction with specific platelet membrane receptors. Multiple domains of von Willebrand factor and fibrinogen are involved in securing initiation and growth of platelet thrombi.     

The impact of self-efficacy on behavior change and weight change among overweight participants in a weight loss trial.

Despite considerable clinical interest, attempts to link perceived self-efficacy with successful weight control have had mixed success. Definitive data on prospective associations between self-efficacy and weight loss are particularly sparse. This study examined relationships between self-efficacy beliefs, weight control behaviors, and weight change among individuals participating in a weight loss trial (N = 349, 87% women). Cross-sectionally, eating and exercise self-efficacy beliefs were strongly associated with corresponding weight loss behaviors. Self-efficacy beliefs prospectively predicted weight control behavior and weight change during active treatment but not during follow-up. Mediational models indicate that people's weight control behaviors mediate the impact of self-efficacy on weight change. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In-vitro effect of oncostatin M on the release by endothelial cells of von Willebrand factor, tissue-type plasminogen activator and plasminogen activator inhibitor-1

Epidemiological studies have demonstrated that levels of plasma fibrinogen, von Willebrand factor (vWf), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) are associated with the incidence of vascular disease. Since oncostatin M dramatically induces fibrinogen biosynthesis by hepatocytes and could be implicated in vascular injury leading to atherosclerosis, we have analyzed the effect of oncostatin M on PAI-1, vWf and tPA secretion by endothelial cells. A 2-h incubation of human umbilical vein endothelial cells with oncostatin M increases thrombin-induced secretion of vWf to the same extent as tumour necrosis factor-alpha or interleukin-1 (137+/-26% of control for 5 ng/ml oncostatin M, P < 0.001, n=5). The effects on tPA and PAI-1 secretion were different depending on the type of endothelial cells tested. On human umbilical vein endothelial cells, oncostatin M induced an increase in PAI-1 and a decrease in tPA secretion, which could explain the thrombogenicity of oncostatin M on large vessels. On a human microvasculature endothelial cell line, oncostatin M did not modify PAI-1 but induced an increase in tPA secretion. This observation of the effects of oncostatin M on both macro- and microvasculature could explain the increased levels of vWf, PAI-1 and tPA in the plasma of atherosclerotic subjects identified in epidemiological studies, suggesting that oncostatin M could play a key role in the development of atherosclerotic lesions.     

Instability in the ATCT variable number tandem repeat locus VWF.VNTR I in intron 40 of von Willebrand factor gene

The von Willebrand factor gene intron 40 variable number tandem repeat VWF.VNTR I exhibits 10 alleles making it highly polymorphic and useful for parentage and forensic testing, 45 unrelated families (210 meiotic events) were tested for VWF.VNTR I alleles. One spontaneous mutation was observed in a family member. Haplotype analysis demonstrated that this mutation was due to a gain of one motif repeat by a paternal allele. Sequence analysis confirmed the difference in the number of motif repeats between the proband and the alleles expressed by the parents. This instability emphasizes the importance of demonstrating exclusion in at least two separate loci in parentage testing.     

Type 2M von Willebrand disease: F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin- but not botrocetin-mediated binding of von Willebrand factor to platelets

von Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have borderline or low vWF antigen levels, normal vWF multimer patterns, disproportionately low ristocetin cofactor activity, and significant bleeding symptoms. Whereas ristocetin-induced binding of plasma vWF from affected members of both families to fixed platelets was reduced, botrocetin-induced platelet binding was normal. The sequencing of genomic DNA identified unique missense mutations in each family in the vWF exon 28. In Family A, a missense mutation at nucleotide 4105T --> A resulted in a Phe606Ile amino acid substitution (F606I) and in Family B, a missense mutation at nucleotide 4273A --> T resulted in an Ile662Phe amino acid substitution (I662F). Both mutations are within the large disulfide loop between Cys509 and Cys695 in the A1 domain that mediates vWF interaction with platelet glycoprotein Ib. Expression of recombinant vWF containing either F606I or I662F mutations resulted in mutant recombinant vWF with decreased ristocetin-induced platelet binding, but normal multimer structure, botrocetin-induced platelet binding, collagen binding, and binding to the conformation-sensitive monoclonal antibody, AvW-3. Both mutations are phenotypically distinct from the previously reported variant type 2MMilwaukee-1 because of the presence of normal botrocetin-induced platelet binding, collagen binding, and AvW-3 binding, as well as the greater frequency and intensity of clinical bleeding. When the reported type 2M mutations are mapped on the predicted three-dimensional structure of the A1 loop of vWF, the mutations cluster in one region that is distinct from the region in which the type 2B mutations cluster.     

Relationship between weight change in young adulthood and the risk of NIDDM. The Sotetsu Study

OBJECTIVE: To investigate the independent effect of weight change in young adulthood on the risk of prevalent NIDDM among middle-aged Japanese men. RESEARCH DESIGN AND METHODS: A case-control study was carried out in 895 male employees aged > or = 30 years of a railway company located in the vicinity of Tokyo. Adjusted odds ratios (ORs) were calculated for prevalent diabetes in each category of weight change (obtained from subjects' medical records) in young adulthood and adulthood. Adjustment for current age, initial BMI, and weight change in each age stratum was performed by the Mantel-Haenszel method or multiple logistic regression analysis. RESULTS: Weight change between 20 years of age and the age at maximum weight was not associated with the risk of NIDDM. Weight gain between 20 and 25 years of age was significantly and positively associated with the risk of NIDDM (OR 3.87 for gains > or = 10.0 kg, 2.53 for gains of 5.0-9.9%, and 3.73 for gains > or = 10.0%). On the other hand, moderate weight gain after 30 years of age was significantly inversely associated with NIDDM (OR 0.44 for gains of 5.0-9.9 kg, 0.15 for gains of 10.0-19.9%, and 0.38 for gains of 20.0-29.9%). CONCLUSIONS: Extreme weight gain between 20 and 25 years of age is a significant predictor of NIDDM, independent of current age, BMI at 20 years of age, and weight change within other age strata.