Docosahexaenoic acid-enriched canola oil increases adiponectin concentrations: a randomized crossover controlled intervention trial.

BACKGROUND AND AIMS: Little is known about the effect of various dietary fatty acids on pro- and anti-inflammatory processes. We investigated the effect of 5 oils containing various amounts of alpha-linolenic acid (ALA), linoleic acid (LA), oleic acid (OA) and docosahexaenoic acid (DHA) on plasma inflammatory biomarkers and expression levels of key inflammatory genes and transcription factors in whole blood cells. METHODS AND RESULTS: In a randomized, crossover controlled nutrition intervention, 114 adult men and women with abdominal obesity and at least one other criterion for the metabolic syndrome consumed 5 experimental isoenergetic diets for 4 weeks each, separated by 4-week washout periods. Each diet provided 60 g/3000 kcal of different oils: 1) control corn/safflower oil blend (CornSaff; LA-rich), 2) flax/safflower oil blend (FlaxSaff; ALA-rich), 3) conventional canola oil (Canola; OA-rich), 4) high oleic canola oil (CanolaOleic; highest OA content), 5) DHA-enriched high oleic canola oil (CanolaDHA; OA- and DHA-rich). Gene expression in whole blood cells was assessed in a subset of 62 subjects. CanolaDHA increased plasma adiponectin concentrations compared with the control CornSaff oil treatment (+4.5%, P = 0.04) and FlaxSaff (+6.9%, P = 0.0008). CanolaDHA also reduced relative expression levels of interleukin (IL)1B compared with CornSaff and Canola (-11% and -13%, respectively, both P = 0.03). High-sensitivity C-reactive protein concentrations were lower after Canola than after FlaxSaff (-17.8%, P = 0.047). CONCLUSION: DHA-enriched canola oil exerts anti-inflammatory effects compared with polyunsaturated fatty acids from plant sources.

Altering source or amount of dietary carbohydrate has acute and chronic effects on postprandial glucose and triglycerides in type 2 diabetes: Canadian trial of Carbohydrates in Diabetes (CCD).

BACKGROUND AND AIMS: Nutrition recommendations for type 2 diabetes (T2DM) are partly guided by the postprandial responses elicited by diets varying in carbohydrate (CHO). We aimed to explore whether long-term changes in postprandial responses on low-glycemic-index (GI) or low-CHO diets were due to acute or chronic effects in T2DM. METHODS AND RESULTS: Subjects with diet-alone-treated T2DM were randomly assigned to high-CHO/high-GI (H), high-CHO/low-GI (L), or low-CHO/high-monounsaturated-fat (M) diets for 12-months. At week-0 (Baseline) postprandial responses after H-meals (55% CHO, GI = 61) were measured from 0800 h to 1600 h. After 12 mo subjects were randomly assigned to H-meals or study diet meals (L, 57% CHO, GI = 50; M, 44% CHO, GI = 61). This yielded 5 groups: H diet with H-meals (HH, n = 34); L diet with H- (LH, n = 17) or L-meals (LL, n = 16); and M diet with H- (MH, n = 18) or M meals (MM, n = 19). Postprandial glucose fluctuations were lower in LL than all other groups (p < 0.001). Changes in postprandial-triglycerides differed among groups (p < 0.001). After 12 mo in HH and MM both fasting- and postprandial-triglycerides were similar to Baseline while in MH postprandial-triglycerides were significantly higher than at Baseline (p = 0.028). In LH, triglycerides were consistently (0.18-0.34 mmol/L) higher than Baseline throughout the day, while in LL the difference from Baseline varied across the day from 0.04 to 0.36 mmol/L (p < 0.001). CONCLUSION: Low-GI and low-CHO diets have both acute and chronic effects on postprandial glucose and triglycerides in T2DM subjects. Thus, the composition of the acute test-meal and the habitual diet should be considered when interpreting the nutritional implications of different postprandial responses.

Plasma Branched-Chain Amino Acid Concentrations and Glucose Homeostasis in Kidney Transplant Recipients and Candidates.

Background: Post-transplant diabetes mellitus (PTDM) encompasses new-onset and previously unrecognized type 2 diabetes. Kidney failure masks type 2 diabetes. Branched-chain amino acids (BCAA) are closely associated with glucose metabolism. Therefore, understanding BCAA metabolism both in kidney failure and after kidney transplantation may inform PTDM mechanisms. Objective: To understand the impact of present or absent kidney function on plasma BCAA concentrations. Design: Cross-sectional study of kidney transplant recipients and kidney transplant candidates. Setting: Large kidney transplant center in Toronto, Canada. Measurements: We measured plasma BCAA and aromatic amino acid (AAA) concentrations in 45 pre-kidney transplant candidates (15 with type 2 diabetes, 30 without type 2 diabetes) and 45 post-kidney transplant recipients (15 PTDM, 30 non-PTDM), along with insulin resistance and sensitivity by 75 g oral glucose loading for those in each group without type 2 diabetes. Methods: Plasma AA concentrations were analyzed using MassChrom AA Analysis and compared between groups. The insulin sensitivity for oral glucose tolerance tests or Matsuda index (a measure of whole-body insulin resistance), Homeostatic Model Assessment for Insulin Resistance (a measure of hepatic insulin resistance), and Insulin Secretion-Sensitivity Index-2 (ISSI-2, a measure of pancreatic ß-cell response) was calculated from fasting insulin and glucose concentrations, and compared with BCAA concentrations. Results: Each BCAA concentration was higher in post-transplant subjects than pre-transplant subjects (P < .001 for leucine, isoleucine, valine). In post-transplant subjects, each BCAA concentration was higher in PTDM versus non-PTDM (odds ratio for PTDM 3-4 per 1 SD increase in BCAA concentration, P < .001 for each). Tyrosine concentrations were also higher in post-transplant subjects than pre-transplant subjects, but tyrosine did not differ by PTDM status. By contrast, neither BCAA nor AAA concentrations were different in pre-transplant subjects with or without type 2 diabetes. Whole-body insulin resistance, hepatic insulin resistance, and pancreatic ß-cell response did not differ between nondiabetic post-transplant and pre-transplant subjects. Branched-chain amino acid concentrations correlated with the Matsuda index and Homeostatic Model Assessment for Insulin Resistance (P < .05 for each) only in nondiabetic post-transplant subjects-not in nondiabetic pre-transplant subjects. Branched-chain amino acid concentrations did not correlate with ISSI-2 in either pre-transplant or post-transplant subjects. Limitations: The sample size was small, and subjects were not studied prospectively for the development of type 2 diabetes. Conclusions: Plasma BCAA concentrations are higher post-transplant in type 2 diabetic states, but do not differ by diabetes status in the presence of kidney failure. The association of BCAA with measures of hepatic insulin resistance among nondiabetic post-transplant patients is consistent with impaired BCAA metabolism as a characteristic of kidney transplantation.

Contexte: Le diabète post-transplantation (DPT) englobe les nouvelles manifestations du diabète de type 2 nouveau et le diabète précédemment non reconnu. L'insuffisance rénale masque le diabète de type 2. Les acides aminés à chaîne ramifiée (AACR) sont étroitement liés au métabolisme du glucose. Par conséquent, la compréhension du métabolisme des acides aminés à chaîne ramifiée (AACR) à la fois dans l'insuffisance rénale et après la transplantation rénale peut informer les mécanismes de DPT. Objectifs: Comprendre l'impact de la présence ou de l'absence de fonction rénale sur les concentrations plasmatiques d'AACR. Type d'étude: Étude transversale portant sur des receveurs d'une greffe rénale et des candidats à une transplantation de rein. Cadre: Un grand centre de transplantation rénale de Toronto (Canada). Mesures: Nous avons mesuré les concentrations plasmatiques d'AACR et d'AA aromatiques (AAA) chez 45 candidats pré-transplantation rénale (15 atteints de diabète de type 2; 30 non-diabétiques) et 45 patients ayant reçu une greffe rénale (15 DPT, 30 non-DPT). Les patients des groupes non-diabétiques ont en outre subi un test de résistance et de sensibilité à l'insuline à la suite de l'administration orale de 75 g de glucose. Méthodologie: Les concentrations plasmatiques d'AA ont été analysées à l'aide de l'appareil Mass Chrom AA Analysis et comparées entre les groupes. La sensibilité à l'insuline pour les tests oraux de tolérance au glucose ou l'indice Matsuda (mesure de la résistance à l'insuline dans tout l'organisme), l'évaluation du modèle homéostatique de la résistance à l'insuline (mesure de la résistance hépatique à l'insuline) et l'indice de sensibilité à la sécrétion d'insuline-2 (mesure de la réponse des cellules ß pancréatiques) ont été calculés à partir des concentrations d'insuline et de glucose à jeun, et comparés aux concentrations d'AACR. Résultats: Chacune des concentrations en AACR était plus élevée chez les sujets post-transplantation que chez les sujets pré-transplantation (p < 0,001 pour la leucine, l'isoleucine, la valine). Chez les sujets post-transplantation, chaque concentration d'AACR était plus élevée chez les sujets DPT que chez le cas des sujets non-DPT (RC pour DPT: entre 3 et 4 pour chaque augmentation de l'écart-type; p < 0,001 pour chacun). Les concentrations de tyrosine étaient également plus élevées chez les sujets post-transplantation que chez les sujets pré-transplantation, mais ne différaient pas selon le statut du DPT. En revanche, ni les concentrations d'AACR ni les concentrations d'AAA n'étaient différentes chez les sujets pré-transplantation qu'ils soient ou non atteints de diabète de type 2. La résistance de tout l'organisme à l'insuline, la résistance hépatique à l'insuline et la réponse des cellules ß pancréatiques ne différaient pas entre les sujets non-diabétiques avant ou après la transplantation. Les concentrations d'AACR étaient corrélées avec l'indice Matsuda et l'évaluation du modèle homéostatique de la résistance à l'insuline (p<0,05 pour chacun) uniquement chez les sujets non-diabétiques après la transplantation, et non chez les sujets non-diabétiques avant la transplantation. Les concentrations d'AACR n'étaient pas en corrélation avec l'ISSI-2, que ce soit chez les sujets avant ou après la transplantation. Limites: L'échantillon était de petite taille et les sujets n'ont pas été étudiés prospectivement pour le développement du diabète de type 2. Conclusion: Les concentrations plasmatiques d'AACR sont plus élevées après la transplantation chez les sujets diabétiques de type 2, mais ne diffèrent pas selon le statut du diabète en présence d'une insuffisance rénale. Les associations entre les AACR et les mesures de la résistance hépatique à l'insuline chez les patients non-diabétiques post-transplantation sont cohérentes avec une altération du métabolisme des AACR comme caractéristique de la transplantation rénale.

Utility of non-high-density lipoprotein cholesterol in assessing incident type 2 diabetes risk.

AIMS: Traditional lipid indices have been associated with type 2 diabetes, but limited data are available regarding non-high-density lipoprotein (non-HDL) cholesterol. In view of recent guidelines for the clinical management of dyslipidemia recommending the monitoring of non-HDL cholesterol as a secondary target after achieving the low-density lipoprotein (LDL) cholesterol goal, we aimed to assess the association of non-HDL cholesterol with incident type 2 diabetes and compare its utility as a risk predictor with traditional lipid variables in Aboriginal Canadians. METHODS: Of 606 diabetes-free participants at baseline, 540 (89.1%) returned for 10-year follow-up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipids were measured. Fasting and 2-h postload glucose were obtained at baseline and follow-up to determine the incidence of type 2 diabetes. RESULTS: The cumulative incidence of type 2 diabetes was 17.5%. Higher non-HDL cholesterol, total-to-HDL cholesterol ratio, apolipoprotein B, triglyceride and LDL cholesterol and lower HDL cholesterol concentrations were individually associated with incident type 2 diabetes in univariate analyses (all p < 0.05). Non-HDL cholesterol was a superior determinant of incident diabetes compared with LDL cholesterol (comparing C-statistics of univariate models p = 0.01) or HDL cholesterol (p = 0.004). With multivariate adjustment including waist circumference, non-HDL cholesterol remained associated with incident diabetes [odds ratio (OR) 1.42 (95% confidence interval, CI 1.07-1.88)], while LDL cholesterol and HDL cholesterol became non-significant. CONCLUSIONS: Non-HDL cholesterol was associated with incident type 2 diabetes and was superior to LDL cholesterol as a risk predictor in this population. Further studies are required to establish the utility of non-HDL cholesterol in non-Aboriginal populations.

The postpartum cardiovascular risk factor profile of women with isolated hyperglycemia at 1-hour on the oral glucose tolerance test in pregnancy.

BACKGROUND AND AIMS: Women with gestational diabetes mellitus (GDM) have an enhanced cardiovascular risk factor profile at 3-months postpartum and an elevated risk of future cardiovascular disease, as compared to their peers. Recently, it has emerged that even mild dysglycemia on antepartum oral glucose tolerance test (OGTT) predicts an increased risk of future cardiovascular disease, although it is not known whether there exists an identifiable high-risk subgroup within this patient population. Since gestational impaired glucose tolerance (GIGT) due to isolated hyperglycemia at 1-h during the OGTT (1-h GIGT) bears metabolic similarity to GDM, we hypothesized that, like GDM, 1-h GIGT may predict a high-risk postpartum cardiovascular phenotype. METHODS AND RESULTS: In this prospective cohort study, 485 women underwent antepartum OGTT, followed by cardiovascular risk factor assessment at 3-months postpartum. The antepartum OGTT identified 4 gestational glucose tolerance groups: GDM (n = 137); 1-h GIGT (n = 39); GIGT at 2- or 3-h (2/3-h GIGT)(n = 50); and normal glucose tolerance (NGT)(n = 259). After adjustment for age, ethnicity, breastfeeding and waist circumference, mean levels of the following cardiovascular risk factors progressively increased from NGT to 2/3-h GIGT to 1-h GIGT to GDM: LDL cholesterol (p = 0.0026); total cholesterol:HDL (p = 0.0030); apolipoprotein B (p = 0.004); apolipoprotein B:apolipoprotein A1 (p = 0.026); leptin (p = 0.018); and C-reactive protein (p = 0.011). CONCLUSIONS: Amongst women without GDM, 1-h GIGT predicts an enhanced postpartum cardiovascular risk factor profile. It thus emerges, that amongst young women with mild dysglycemia in pregnancy, those with 1-h GIGT may comprise an unrecognized patient population at risk for future cardiovascular disease.

Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia.

AIMS/HYPOTHESIS: The postpartum phase following gestational diabetes (GDM) is characterised by subtle metabolic defects, including the beta cell dysfunction that is believed to mediate the increased future risk of type 2 diabetes in this patient population. Low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have recently emerged as novel diabetic risk factors, although their relevance to GDM and subsequent diabetes has not been characterised. Thus, we sought to determine whether adiponectin, leptin and CRP levels during pregnancy relate to the postpartum metabolic defects linking GDM with type 2 diabetes. METHODS: Metabolic characterisation, including oral glucose tolerance testing, was undertaken in 487 women during pregnancy and at 3 months postpartum. Based on the antepartum OGTT, there were 137 women with GDM, 91 with gestational impaired glucose tolerance and 259 with normal glucose tolerance. RESULTS: Adiponectin levels were lowest (p < 0.0001) and CRP levels highest (p = 0.0008) in women with GDM. Leptin did not differ between the glucose tolerance groups (p = 0.4483). Adiponectin (r = 0.41, p < 0.0001), leptin (r = -0.36, p < 0.0001) and CRP (r = -0.30, p < 0.0001) during pregnancy were all associated with postpartum insulin sensitivity (determined using the insulin sensitivity index of Matsuda and DeFronzo [IS(OGTT)]). Intriguingly, adiponectin levels were also related to postpartum beta cell function (insulinogenic index/HOMA of insulin resistance; r = 0.16, p = 0.0009). Indeed, on multiple linear regression analyses, adiponectin levels during pregnancy independently predicted both postpartum insulin sensitivity (t = 3.97, p < 0.0001) and beta cell function (t = 2.37, p = 0.0181), even after adjustment for GDM. Furthermore, adiponectin emerged as a significant negative independent determinant of postpartum fasting glucose (t = -3.01, p = 0.0027). CONCLUSIONS/INTERPRETATION: Hypoadiponectinaemia during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia, and hence may be relevant to the pathophysiology relating GDM with type 2 diabetes.

Paraoxonase 1 arylesterase activity and mass are reduced and inversely related to C-reactive protein in patients on either standard or home nocturnal hemodialysis.

UNLABELLED: Human serum paraoxonase (PON1) activity is reduced in standard hemodialysis (SHD) (4 hours, 3 days/week) patients. Home nocturnal hemodialysis (HNHD) (8 hours, 6 days/week), provides a greater dialysis dose resulting in a greater clearance of metabolites. Whether improvements in the metabolic milieu of HNHD patients results in different PON1 activity levels compared to SHD patients is unclear. We determined serum PON1 mass and arylesterase activities in a group of HNHD patients and compared them to SHD patients and a group of healthy controls (HC). PATIENTS AND METHODS: We measured PON1 arylesterase activity and mass, C-reactive protein (CRP), cystatin C, total and high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins A-I and B in 15 HNHD, 15 SHD and 15 HC participants. RESULTS: PON1 arylesterase activity (p < 0.001) and mass (p < 0.05) were significantly higher in HC participants compared to SHD and HNHD participants, although no significant differences were noted between HD groups. CRP (p < 0.05) was significantly higher in SHD compared to HC participants and there were no significant differences noted between HD groups. Cystatin C (p < 0.001) was significantly different among the 3 groups. There were no significant differences noted in any lipoprotein parameters among the groups. PON1 activity (r = -0.636, p < 0.001) and mass (r = -0.425, p = 0.019) were inversely correlated with CRP in HD patients. CONCLUSION: PON1 is reduced in HNHD patients compared to HC subjects, independent of the concentration of HDL cholesterol. Within subjects on HD, the combination of increased CRP and reduced PON1 may identify subjects at a high risk for cardiovascular complications.

Effect of short-term intensive insulin therapy on the incretin response in early type 2 diabetes.

AIMS: Short-term intensive insulin therapy (IIT) and gastric bypass surgery are both interventions that can improve beta-cell function, reduce insulin resistance and induce remission of type 2 diabetes. Whereas gastric bypass yields an enhanced glucagon-like peptide-1 (GLP-1) response that may contribute to its metabolic benefits, the effect of short-term IIT on the incretin response is unclear. Thus, we sought to evaluate the impact of IIT on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion in early type 2 diabetes. METHODS: In this study, 63 patients (age 59±8.3 years, baseline A1c 6.8±0.7%, diabetes duration 3.0±2.1 years) underwent 4 weeks of IIT (basal insulin detemir and pre-meal insulin aspart). GLP-1, GIP and glucagon responses were assessed by the area-under-the-curve (AUC) of these hormones on oral glucose tolerance tests at baseline and 1-day after the completion of therapy. Beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), with insulin resistance measured by Homeostasis Model Assessment (HOMA-IR). RESULTS: As expected, comparing the post-therapy oral glucose tolerance test to that at baseline, IIT increased ISSI-2 (P=0.02), decreased HOMA-IR (P<0.001), and reduced AUCglucagon (P<0.001). Of note, however, IIT had no significant impact on AUCGLP-1 (P=0.24) and reduced AUCGIP (P=0.02). CONCLUSION: Despite improving beta-cell function, insulin resistance and glucagonemia, short-term IIT does not change GLP-1 secretion and decreases the GIP response to an oral glucose challenge in early type 2 diabetes. Thus, the beneficial impact of this therapy on glucose homeostasis is not attributable to its effects on incretin secretion.

Apolipoprotein CIISt. Michael. Familial apolipoprotein CII deficiency associated with premature vascular disease.

A 60-yr-old woman and her brother, products of a consanquinous mating, were chylomicronemic. The chylomicronemia in both subjects was found to be due to the absence of functional apoCII. A mutant form, designated apoCIISt. Michael (apoCIIs), was identified by two-dimensional electrophoresis and Western blot using anti-apoCII antiserum. The isoelectric point of apoCIIs was similar to that of normal apoCII, but its apparent molecular weight was 3,000 greater. Tryptic peptides of apoCIIs were identified that had retention times in reverse-phase high pressure liquid chromatography and amino acid compositions indistinguishable from that of residues 1 to 48 and 51 to 55 of normal apoCII. The complete sequence of apoCIIs was deduced from a combination of the sequence analysis of tryptic peptides corresponding to residues 56 through 96 and the known sequence of the apoCII gene. ApoCIIs differed from apoCII at residue 70 where Gln70 was replaced by Pro70 and the sequence terminated with Pro96. This is consistent with a base insertion in the codon for Asp69 or Gln70 in the apoCII gene and a subsequent translation reading frame shift. Both patients were homozygous for apoE-4. This and the absence of normal apoCII is consistent with homozygozity at the apoE-CII gene locus on chromosome 19. Both siblings and several relatives had premature ischemic vascular disease, in contrast with its apparent absence in other apoCII-deficient families.

Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia.

We report a Canadian kindred with a novel mutation in the apolipoprotein (apo) A-I gene causing analphalipoproteinemia. The 34-yr-old proband, product of a consanguineous marriage, had bilateral retinopathy, bilateral cataracts, spinocerebellar ataxia, and tendon xanthomata. High density lipoprotein cholesterol (HDL-C) was < 0.1 mM and apoA-I was undetectable. Genomic DNA sequencing of the proband's apoA-I gene identified a nonsense mutation at codon [-2], which we designate as Q[-2]X. This mutation causes a loss of endonuclease digestion sites for both BbvI and Fnu4HI. Genotyping identified four additional homozygotes, four heterozygotes, and two unaffected subjects among the first-degree relatives. Q[-2]X homozygosity causes a selective failure to produce any portion of mature apoA-I, resulting in very low plasma level of HDL. Heterozygosity results in approximately half-normal apoA-I and HDL. Gradient gel electrophoresis and differential electroimmunodiffusion assay revealed that the HDL particles of the homozygotes had peak Stokes diameter of 7.9 nm and contained apoA-II without apoA-I (Lp-AII). Heterozygotes had an additional fraction of HDL3-like particles. Two of the proband's affected sisters had documented premature coronary heart disease. This kindred, the third reported apoA-I gene mutation causing isolated complete apoA-I deficiency, appears to be at significantly increased risk for atherosclerosis.

A major role for VCAM-1, but not ICAM-1, in early atherosclerosis.

VCAM-1 and ICAM-1 are endothelial adhesion molecules of the Ig gene superfamily that may participate in atherogenesis by promoting monocyte accumulation in the arterial intima. Both are expressed in regions predisposed to atherosclerosis and at the periphery of established lesions, while ICAM-1 is also expressed more broadly. To evaluate functions of VCAM-1 in chronic disease, we disrupted its fourth Ig domain, producing the murine Vcam1(D4D) allele. VCAM-1(D4D) mRNA and protein were reduced to 2-8% of wild-type allele (Vcam1(+)) levels but were sufficient to partially rescue the lethal phenotype of VCAM-1-null embryos. After crossing into the LDL receptor-null background, Vcam1(+/+) and Vcam1(D4D/D4D) paired littermates were generated from heterozygous intercrosses and fed a cholesterol-enriched diet for 8 weeks. The area of early atherosclerotic lesions in the aorta, quantified by en face oil red O staining, was reduced significantly in Vcam1(D4D/D4D) mice, although cholesterol levels, lipoprotein profiles, and numbers of circulating leukocytes were comparable to wild-type. In contrast, deficiency of ICAM-1 either alone or in combination with VCAM-1 deficiency did not alter nascent lesion formation. Therefore, although expression of both VCAM-1 and ICAM-1 is upregulated in atherosclerotic lesions, our data indicate that VCAM-1 plays a dominant role in the initiation of atherosclerosis.

Contribution of hierarchical clustering techniques to the modeling of the geographic distribution of genetic polymorphisms associated with chronic inflammatory diseases in the Québec population.

OBJECTIVES: The purpose of this project was to evaluate the potential of the downward hierarchical clustering analysis (DHCA) for studying genetic heterogeneity, i.e. differences in allele frequency in subpopulations, such as the 15 public health regions of the province of Québec (Canada). METHODS: The study relied on an anonymized sample of 1,680 individuals who had participated in the Québec Heart Health Survey in 1990-1991. The genotyping of 11 variants in 8 candidate genes known to be involved in chronic inflammatory diseases, namely asthma and cardiovascular diseases, was performed using the amplification refractory mutation system and restriction fragment length polymorphism techniques. Only variants showing an allelic frequency >2% in the Québec Heart Health Survey (n = 8) were selected. DHCA techniques were then applied to model the geographical distribution of these 8 genetic variants in 15 Québec public health regions and to study genetic heterogeneity. RESULTS: The DHCA allowed to group public health regions and gene variants on the basis of genetic variability. For both asthma and cardiovascular diseases, 3 significant clusters of public health regions and 1 cluster of gene variants were identified. DISCUSSION: This study suggests that DHCA might be useful in studying genetic heterogeneity at the population level and for public health activities.

Differential impact of maternal and paternal ethnicity on the pattern of fat distribution in infants at age 3 months.

BACKGROUND: As ethnicity is typically recorded as a single demographic variable in clinical studies, little is known about the relative impact of maternal vs. paternal ethnicity on fat distribution. OBJECTIVES: The objective of this study was to determine whether there is a differential impact of maternal and paternal ethnicity on infant adiposity. METHODS: Three hundred fifty-five infants underwent anthropometric assessment at age 3 months, including skin-fold thickness (SFT) measurement at subscapular, suprailiac and triceps. Maternal (M) and paternal (P) ethnicity were classified as white (M = 241, P = 252), Asian (M = 50, P = 42) or other (M = 64, P = 61). RESULTS: Infants with either Asian mother (compared with white) or Asian father (compared with white) had increased subscapular, suprailiac and triceps SFT (all P < 0.05). On logistic regression analysis, however, only maternal Asian ethnicity (compared with white) independently predicted the likelihood of an infant being in the highest tertile for SFT at subscapular (odds ratio [OR] = 2.72, 95% confidence interval 1.17-6.34, P = 0.02), suprailiac (OR = 3.56, 1.51-8.42, P = 0.004) and triceps (OR = 3.26, 1.40-7.55, P = 0.005). In contrast, paternal Asian ethnicity was independently associated with sum of SFT only (OR = 2.46, 1.02-5.97, P = 0.04). CONCLUSION: Maternal and paternal Asian ethnicity have differential effects on infant fat distribution. Future clinical studies on obesity and fat composition should consider the distinct contributions of both parents to the ethnic classification of participants.

Hepatic fat and abdominal adiposity in early pregnancy together predict impaired glucose homeostasis in mid-pregnancy.

Hepatic fat and abdominal adiposity individually reflect insulin resistance, but their combined effect on glucose homeostasis in mid-pregnancy is unknown. A cohort of 476 pregnant women prospectively underwent sonographic assessment of hepatic fat and visceral (VAT) and total (TAT) adipose tissue at 11-14 weeks' gestation. Logistic regression was used to assess the relation between the presence of maternal hepatic fat and/or the upper quartile (Q) of either VAT or TAT and the odds of developing the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or gestational diabetes mellitus at 24-28 weeks' gestation, based on a 75 g OGTT. Upon adjusting for maternal age, ethnicity, family history of DM and body mass index (BMI), the co-presence of hepatic fat and quartile 4 (Q4) of VAT (adjusted odds ratio (aOR) 6.5, 95% CI: 2.3-18.5) or hepatic fat and Q4 of TAT (aOR 7.8 95% CI 2.8-21.7) were each associated with the composite outcome, relative to women with neither sonographic feature. First-trimester sonographic evidence of maternal hepatic fat and abdominal adiposity may independently predict the development of impaired glucose homeostasis and GDM in mid-pregnancy.

Differential transfer of C and E apolipoproteins from very-low-density lipoprotein to lysophosphatidylcholine-phosphatidylcholine micelles.

Rat plasma VLDL was incubated with lysoPC/PC micelles consisting of 45-90 mol% lysoPC at micelle/VLDL phospholipid ratios of 0.33-6. Following incubation, the VLDL and micellar particles were reisolated by ultracentrifugation and the lipid and apolipoprotein composition determined by high-temperature gas chromatography and polyacrylamide gel electrophoresis, respectively. Lysophosphatidylcholine was found to equilibrate between the very-low-density lipoproteins and micellar fraction without transfer of phosphatidylcholine or sphingomyelin between these fractions. This produced reisolated VLDL and micellar particles with nearly identical lysoPC/PC ratios. Only apolipoprotein E transferred to reisolated micellar fractions with less than 35 mol% lysoPC. The C apolipoproteins were also transferred to the micellar fraction when the reisolated micelles contained more than 35 mol% lysoPC. It is concluded that apolipoproteins E and C can bind to HDL-size micellar particles of appropriate composition. The differential transfer of apolipoproteins E and C indicates that fundamental differences exist between these apolipoproteins in their interaction with lipid interfaces.

Effect of core composition and particle size of lipid emulsions on apolipoprotein transfer of plasma lipoproteins in vivo.

Lipid emulsions corresponding in size and surface composition to chylomicron and low density lipoprotein but differing in lipid core composition were injected into rats a tail vein cannula and 10 min later blood was withdrawn via the abdominal aorta. Plasma lipoproteins were isolated by ultracentrifugation and the lipid and apolipoprotein composition was determined by gas-liquid chromatography and gel electrophoresis, respectively. It was found that apolipoprotein C peptides were transferred to Sf greater than 400 particles of large diameter regardless of whether their cores contained cholesteryl esters or triacylglycerols, but not to Sf greater than 400 particles of small diameter. Apolipoprotein A-I transferred to both large and small diameter cholesteryl ester core particles but only to larger diameter triacylglycerol core particles. In contrast, apolipoprotein E became associated with small and large diameter particles regardless of core composition. In addition, all Sf greater than 400 fractions contained significant amounts of apopeptides with molecular weights greater than 45 000, which did not correspond to the common apolipoproteins. This is the first study to prove systematically the effects of lipid composition and particle size on apolipoprotein transfer in vivo.

Direct comparison of dietary portfolio vs statin on C-reactive protein.

BACKGROUND: 3-Hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) markedly reduce serum cholesterol and have anti-inflammatory effects. The effect of cholesterol-lowering diets on inflammatory biomarkers is less well known. OBJECTIVE: To compare the efficacy of a dietary combination (portfolio) of cholesterol-lowering foods vs a statin in reducing C-reactive protein (CRP) as a biomarker of inflammation linked to increased cardiovascular disease risk. METHODS: In all, 34 hyperlipidemic subjects completed three 1-month treatments as outpatients in random order: a very low-saturated fat diet (control); the same diet with 20 mg lovastatin (statin); and a diet high in plant sterols (1.0 g/1000 kcal), soy protein (21.4 g/1000 kcal), viscous fibers (9.8 g/1000 kcal), and almonds (14 g/1000 kcal) (portfolio). Fasting blood samples were obtained at weeks 0, 2, and 4. RESULTS: Using the complete data, no treatment reduced serum CRP. However, when subjects with CRP levels above the 75th percentile for previously reported studies (> 3.5 mg/l) were excluded, CRP was reduced similarly on both statin, -16.3 +/- 6.7% (n = 23, P = 0.013) and dietary portfolio, -23.8 +/- 6.9% (n = 25, P = 0.001) but not the control, 15.3 +/- 13.6% (n = 28, P = 0.907). The percentage CRP change from baseline on the portfolio treatment (n = 25) was greater than the control (n = 28, P = 0.004) but similar to statin treatment (n = 23, P = 0.349). Both statin and portfolio treatments were similar in reducing CRP and numerically more effective than control but only the change in portfolio was significant after the Bonferroni adjustment. CONCLUSIONS: A combination of cholesterol-lowering foods reduced C-reactive protein to a similar extent as the starting dose of a first-generation statin.

Are Canadian Inuit at increased genetic risk for coronary heart disease?

The Keewatin Inuit of the Northwest Territories of Canada have a very low age-adjusted mortality rate from coronary heart disease. We hypothesized that this apparent protection from disease has a genetic basis. We determined the prevalence of the disease-associated alleles of five candidate genes for atherosclerosis-related phenotypes. Surprisingly, four of the five alleles studied, namely AGT T235, FABP2 T54, PON R192 and APOE E4, were significantly more frequent in a sample of 175 Keewatin Inuit than among a representative control sample of whites living in the region. The high frequencies of these disease-associated alleles suggests either that they have no relationship with disease susceptibility in the Inuit, or that some unmeasured genetic and/or environmental factors mitigate disease susceptibility that is associated with these alleles. This highlights the difficulty in extrapolating findings from one population to another. Also, very modest genotype-phenotype associations were observed between APOE genotype (P = 0.016) and plasma low-density lipoprotein cholesterol concentration and between FABP2 genotype and plasma 2-h postprandial, glucose concentration (P = 0.048). The relationship between APOE alleles and plasma low-density lipoprotein cholesterol was the same as has been previously reported in many study samples. However, the relationship between FABP2 alleles and plasma 2-h postprandial glucose concentrations was the opposite to that reported in other studies. This suggests that differences in environment, such as the type of fatty acid consumed, interacts with functional differences in gene products involved in candidate metabolic pathways to produce phenotypic differences.

Absence of association between genetic variation of the beta 3-adrenergic receptor and metabolic phenotypes in Oji-Cree.

OBJECTIVE: To assess the association between the common missense variant, Y64R, in the gene encoding the beta 3-adrenergic receptor, ADRB3, and intermediate phenotypes related to obesity and NIDDM in Canadian Oji-Cree. RESEARCH DESIGN AND METHODS: We determined genotypes of the ADRB3 Y64R polymorphism in 508 clinically and biochemically well-characterized adult Oji-Cree, of whom 115 had NIDDM. We tested for associations with multivariate analysis of variance. RESULTS: We found the ADRB3 R64 allele frequency to be 0.40 in this population, which is the highest yet observed in a human population. Furthermore, 15% of subjects were R64/R64 homozygotes, compared with a virtual absence of homozygotes in European study samples. However, we found no statistically significant associations of the ADRB3 Y64R genotype either with the presence of NIDDM, with indexes of obesity, or with intermediate quantitative biochemical traits related to NIDDM. CONCLUSIONS: Despite the very high frequency of the ADRB3 R64 allele in this sample of aboriginal people, it was not associated with any metabolic phenotype. This suggests that the ADRB3 R64 allele is probably not a major determinant of obesity or NIDDM in these aboriginal Canadians.