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Background: Expanding evidence indicates that apolipoprotein B (apo B) is superior to LDL cholesterol as a marker of vascular disease. Although traditional lipid measures are known to predict type 2 diabetes, limited data are available regarding apo B. We assessed the association of apo B with incident type 2 diabetes and compared it with traditional lipid variables as a risk predictor in aboriginal Canadians. Methods: Of an initial cohort of 606 individuals without diabetes in 1993–1995, 540 were contacted for the 10-year follow-up evaluation in 2003–2005. Fasting and 2-h postload glucose concentrations were obtained at baseline and follow-up to determine incident type 2 diabetes. Baseline fasting serum lipids were measured with standard laboratory procedures. Results: The cumulative 10-year incidence of type 2 diabetes was 17.5%. High concentrations of apo B, triglycerides, and LDL cholesterol, and low concentrations of HDL cholesterol were individually associated with incident type 2 diabetes in univariate analyses. Comparing C statistics of univariate models showed apo B to be a superior determinant of incident diabetes compared with LDL (P = 0.026) or HDL (P = 0.004) cholesterol. With multivariate adjustment including waist circumference, apo B (odds ratio, 1.50; 95% CI, 1.11–2.02) and triglycerides (odds ratio, 1.49; 95% CI, 1.12–1.98) remained associated with incident diabetes, whereas LDL and HDL cholesterol became nonsignificant. Conclusions: The association of plasma apo B with incident type 2 diabetes and its better prediction of risk compared with LDL or HDL cholesterol suggest the potential for the use of apo B in type 2 diabetes risk communication and prevention.

OBJECTIVE—The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in an Aboriginal Canadian population. RESEARCH DESIGN AND METHODS—Of the 606 Sandy Lake Health and Diabetes Project cohort subjects who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Concentrations of fasting adiponectin, leptin, CRP, IL-6, SAA, and covariates were measured at baseline. Fasting glucose and a 75-g oral glucose tolerance test were obtained at baseline and follow-up to determine incident type 2 diabetes, defined as clinically diagnosed type 2 diabetes or as fasting plasma glucose ≥7.0 mmol/l or 2-h postload plasma glucose ≥11.1 mmol/l at follow-up. RESULTS—Low adiponectin, high leptin, and low adiponectin-to-leptin ratio at baseline were associated with increased risk of incident type 2 diabetes after adjustment for age, sex, triglycerides, HDL cholesterol, hypertension, and impaired glucose tolerance (odds ratio 0.63 [95% CI 0.48–0.83], 1.50 [1.02–2.21], and 0.54 [0.37–0.77], respectively). When the models were additionally adjusted for waist circumference or BMI, however, only low adiponectin remained significantly associated with increased incident diabetes (0.68 [0.51–0.90]). Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction. CONCLUSIONS—Low baseline adiponectin is associated with increased risk of incident type 2 diabetes independent of leptin, CRP, IL-6, SAA, and metabolic syndrome variables including obesity.

Despite a dramatically increasing burden of type 2 diabetes in Aboriginal Canadian communities (1–5), relatively little information is available regarding the prevalence of, and risk factors for, the complications of type 2 diabetes in this population (6). Although previous studies have documented micro- and macrovascular disease in Aboriginal Canadians with diabetes, the majority of these reports have relied heavily on hospital records, chart reviews, and disease registries (6). These approaches may underestimate the magnitude of the complications burden because only those with the severest disease are included, and standardized methods are infrequently used to document complications. The objective of the present research project was to systematically determine, using validated methods, the prevalence of micro- and macrovascular complications among Aboriginal Canadians who have type 2 diabetes and to identify risk factors that are associated with these conditions. The Sandy Lake Diabetes Complications Study has been presented in detail previously (6). Briefly, all community members known to have type 2 diabetes were invited to participate; 189 of 250 (76%) eligible subjects were enrolled, although the sample size varies given time-limited access to certain equipment. Participants were older than nonparticipants and more likely to be male but did not differ in diabetes treatment. Signed informed consent was obtained from all participants, and the study was approved by the Sandy Lake First Nation Band Council and the Mount Sinai Hospital Ethics Review Committee. We used validated measures to assess retinopathy, neuropathy, nephropathy, and cardiovascular disease risk factors, as described previously (6). Digital fundus photography was performed using a nonmydriatic retinal camera, with …

Ultrasound measurements of the carotid wall are widely used surrogate markers for atherosclerosis with the intima-media thickness (IMT) being the most commonly measured variable. However, ultrasound has recently defined carotid artery wall structures in higher spatial dimensions, such as total area of carotid plaques (TPA) and total volume of carotid plaques (TPV). It is possible that IMT, TPA and TPV measure different aspects of the atherosclerotic process and thus have different clinical implications. IMT, TPA and TPV have never been correlated in the same individuals. We had a unique dataset in which IMT, TPA and TPV were measured concurrently in 272 subjects. We evaluated the left and right carotid arterial systems in each subject as independent variables and performed three pairwise correlation analyses between IMT and transformed TPA and TPV from the 544 carotid arterial systems. We found pairwise correlations between IMT and square root TPA, IMT and cubic root TPV and square root TPA and cubic root TPV; these correlation coefficients were 0.667, 0.586 and 0.963, respectively (all P

Background and Purpose— Peroxisome proliferator-activated receptor γ is a crucial molecule in atherogenesis because it is associated with metabolic risk factors such as obesity and diabetes and also plays a key role in subcellular metabolism of arterial wall macrophage foam cells. Genetic variation in PPARG has been associated with metabolic and cardiovascular end points. Methods— We investigated the relationship between 2 common PPARG polymorphisms, namely P12A and c.1431C>T, and carotid atherosclerosis in a sample of 161 Canadian aboriginal people. Dependent variables were carotid intima media thickness (IMT), assessed using B-mode ultrasonography, and total carotid plaque volume (TPV), assessed using 3D ultrasound. Results— Using multivariate analysis, we found that subjects with ≥1 PPARG A12 allele had less carotid IMT than others (0.72±0.03 versus 0.80±0.02 mm; P =0.0045), with no between-genotype difference in TPV. In contrast, subjects with the PPARG c.1431T allele had greater TPV than others (124±18.4 versus 65.1±23.7 mm 3 ; P =0.0079), with no between-genotype difference in IMT. Conclusions— The findings show an association between PPARG genotypes and carotid arterial phenotypes, and further reflect the prevailing view that the PPARG A12 allele protects against deleterious phenotypes. Also, whereas IMT and TPV are somewhat correlated with each other, they might also represent distinct traits with discrete determinants representing different stages of atherogenesis.

This study explores the associations of total, bioavailable, and free 25(OH)D concentrations with dysglycemia, insulin resistance (IR) and β-cell function in an Aboriginal population in Ontario, Canada. We conducted a cross-sectional analysis within the Sandy Lake Health and Diabetes Project (2003-2005). A total of 387 participants (> 12 y) without treated type 2 diabetes mellitus (DM) were assessed for serum total 25(OH)D, fasting plasma glucose and insulin, and anthropometric and lifestyle variables. A 75-g oral glucose tolerance test (OGTT) was administered, with additional blood samples collected at 30-min and 2-hr. Higher serum total 25(OH)D was associated with a decreased prevalence of dysglycemia (odds ratio (OR) 0.68, 95% CI 0.48-0.96 per SD increase). In addition, there were significant associations of total and bioavailable 25(OH)D with measures of insulin action (total 25(OH)D: ISOGTT; β= 0.305; p= 0.001; HOMA IR; β= -0.322; p= 0.001; bioavailable 25(OH)D: ISOGTT; β= 0.183; p= 0.041; HOMA-IR; β...

Background Indigenous populations of Australia and Canada experience disproportionately high rates of chronic disease. Our goal was to compare cardiovascular (CVD) risk profile and diabetes complications from three recent comprehensive studies of diabetes complications in different Indigenous populations in Australia and Canada. Methods We compared participants from three recent studies: remote Indigenous Australians (2002-2003, n = 37 known diabetes), urban Indigenous Australians (2003-2005, n = 99 known diabetes), and remote Aboriginal Canadians (2001-2002, n = 188 known diabetes). Results The three groups were similar for HbA1c, systolic BP, diabetes duration. Although leaner by body-mass-index criteria, remote Indigenous Australians displayed a more adverse CVD risk profile with respect to: waist-hip-ratio (1.03, 0.99, 0.94, remote Indigenous Australians, urban Indigenous Australians, remote Canadians, p < 0.001); HDL-cholesterol (0.82, 0.96, 1.17 mmol/L, p < 0.001); urine albumin-creatinine-ratio (10.3, 2.4, 4.5 mg/mmol); and C-reactive protein. With respect to diabetes complications, microalbuminuria (50%, 25%, 41%, p = 0.001) was more common among both remote groups than urban Indigenous Australians, but there were no differences for peripheral neuropathy, retinopathy or peripheral vascular disease. Conclusions Although there are many similarities in diabetes phenotype in Indigenous populations, this comparison demonstrates that CVD risk profiles and diabetes complications may differ among groups. Irrespective, management and intervention strategies are required from a young age in Indigenous populations and need to be designed in consultation with communities and tailored to community and individual needs.

Background C-reactive protein (CRP), a biomarker of inflammation, has been associated with increased risk of developing cardiovascular disease. Common variants of the hepatocyte nuclear factor 1A (HNF1A) gene encoding HNF-1α have been associated with plasma CRP in predominantly European Caucasian samples. HNF1A might therefore have an impact on vascular disease and diabetes risk that is mediated by CRP. In an Aboriginal Canadian population, a private polymorphism, HNF1A G319S, was associated with increased prevalence of type 2 diabetes. However, it has not been investigated whether this association is mediated by CRP. We aimed to investigate whether CRP was mediating the association between HNF1A G319S and type 2 diabetes in an Aboriginal Canadian population with a high prevalence of diabetes. Methods A total of 718 individuals who participated in a diabetes prevalence and risk factor survey were included in the current analysis. Participants were genotyped for HNF1A G319S. Fasting plasma samples were analyzed for CRP. Fasting plasma glucose and a 75-g oral glucose tolerance test were obtained to determine type 2 diabetes. Results The prevalence rate of type 2 diabetes was 17.4% (125/718) using the 1999 World Health Organization definition and was higher among S319 allele carriers compared to G/G homozygotes (p < 0.0001). Among participants without type 2 diabetes, CRP levels were higher among G/G homozygotes (1.64 [95% confidence interval 1.35-2.00] mg/l) than in S319 carriers (1.26 [1.04-1.54] mg/l) (p = 0.009) after adjustment for age, sex, 2-h post-load glucose, waist circumference, and serum amyloid A. CRP levels were elevated among those with diabetes after similar adjustment (4.39 [95% confidence interval 3.09-6.23] and 4.44 [3.13-6.30] mg/L, respectively), and no significant difference in CRP was observed between S319 carriers and non-carriers (p = 0.95). Conclusions CRP levels were lower in S319 allele carriers of the HNF1A gene compared to non-carriers among individuals without diabetes, but this difference was not present among those with diabetes, who uniformly had elevated CRP levels. Therefore, while HNF1A appears to influence CRP concentrations in the non-diabetic state, chronic elevation of CRP is unlikely mediating the association between the HNF1A polymorphism and the high prevalence of type 2 diabetes in this Aboriginal population.

Expanding evidence indicates that apolipoprotein B (apo B) is superior to LDL cholesterol as a marker of vascular disease. Although traditional lipid measures are known to predict type 2 diabetes, limited data are available regarding apo B. We assessed the association of apo B with incident type 2 diabetes and compared it with traditional lipid variables as a risk predictor in aboriginal Canadians.Of an initial cohort of 606 individuals without diabetes in 1993-1995, 540 were contacted for the 10-year follow-up evaluation in 2003-2005. Fasting and 2-h postload glucose concentrations were obtained at baseline and follow-up to determine incident type 2 diabetes. Baseline fasting serum lipids were measured with standard laboratory procedures.The cumulative 10-year incidence of type 2 diabetes was 17.5%. High concentrations of apo B, triglycerides, and LDL cholesterol, and low concentrations of HDL cholesterol were individually associated with incident type 2 diabetes in univariate analyses. Comparing C statistics of univariate models showed apo B to be a superior determinant of incident diabetes compared with LDL (P = 0.026) or HDL (P = 0.004) cholesterol. With multivariate adjustment including waist circumference, apo B (odds ratio, 1.50; 95% CI, 1.11-2.02) and triglycerides (odds ratio, 1.49; 95% CI, 1.12-1.98) remained associated with incident diabetes, whereas LDL and HDL cholesterol became nonsignificant.The association of plasma apo B with incident type 2 diabetes and its better prediction of risk compared with LDL or HDL cholesterol suggest the potential for the use of apo B in type 2 diabetes risk communication and prevention.

Paraoxonase 1 (PON1) has been reported to be associated with proteinuria in subjects with type 2 diabetes mellitus (T2DM). Plasma cystatin C is more accurate than creatinine for identifying stage 3 kidney disease in T2DM. We tested the hypothesis that PON1 and cystatin C would be associated in T2DM subjects from an Aboriginal Canadian community, who are at high risk for the development of nephropathy. PON1 A(-162)G and PON2 Ala148Gly genotypes, cystatin C, HbA1c, high density lipoprotein cholesterol (HDLC), waist circumference (waist), and duration of diabetes were included in the regression analysis with log(e) (ln) of PON1 mass as the dependent variable. A regression model including PON2 Ala148Gly genotype, HDLC, and ln cystatin C explained 25.8% of the variance in PON1 mass. Conversely, waist, age, ln HbA1c, ln duration of diabetes, and ln PON1 mass, but not PON2 genotype, explained 38% of the variance in cystatin C. Subjects with cystatin C estimated glomerular filtration rate (eGFR) /min per 1.73 m(2) (stage 3 kidney disease) had significantly lower PON1 mass compared with subjects with cystatin C-eGFR >60 ml/min per 1.73 m(2). The lower mass of PON1, an anti-inflammatory HDL-associated enzyme, in T2DM with cystatin C-eGFR /min per 1.73 m(2) may contribute to their increased risk for cardiovascular disease.

Background: Risk factors for type 2 diabetes remain poorly characterized among Aboriginal Canadians. We aimed to determine the incidence of type 2 diabetes in an Aboriginal community and to evaluate prospective associations with metabolic syndrome and its components. Methods: Of 606 participants in the Sandy Lake Health and Diabetes Project from 1993 to 1995 who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipid levels were measured. Fasting and 2-hour postload glucose levels were obtained at follow-up to determine incident cases of type 2 diabetes. Results: The 10-year cumulative incidence of diabetes was 17.5%. High adiposity, dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension at baseline were associated with an increased risk of diabetes after adjustment for age and sex (all p ≤ 0.03). Metabolic syndrome had high specificity (75%–88%) and high negative predictive value (85%–87%) to correctly detect diabetes-free individuals at follow-up. It had low sensitivity (26%–48%) and low positive predictive value (29%–32%) to detect future diabetes. Metabolic syndrome at baseline was associated with incident diabetes after adjustment for age and sex, regardless of whether the syndrome was defined using the National Cholesterol Education Program criteria (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.10–3.75) or the International Diabetes Federation criteria (OR 2.14, 95% CI 1.29–3.55). The association was to the same degree as that for impaired glucose tolerance assessed using the oral glucose tolerance test (OR 2.87, 95% CI 1.52–5.40; p > 0.05 for comparison of C statistics). Interpretation: Metabolic syndrome and its components can be identified with readily available clinical measures. As such, the syndrome may be useful for identifying individuals at risk of type 2 diabetes in remote Aboriginal communities.

Background The metabolic syndrome is associated with increased vascular disease risk. We evaluated two carotid ultrasound measurements, namely intima media thickness and total plaque volume, in a Canadian Oji-Cree population with a high metabolic syndrome prevalence rate. Methods As part of the Sandy Lake Complications Prevalence and Risk Factor Study, 166 Oji-Cree subjects (baseline metabolic syndrome prevalence, 44.0%, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines) were examined using a high-resolution duplex ultrasound scanner. Results Image analysis showed that mean intima media thickness was elevated in subjects with the metabolic syndrome (818 ± 18 vs 746 ± 20 μm), as was total plaque volume (125 ± 26 vs 77.3 ± 17.0 mm3). However, after adjustment for age and sex, the differences were significant only for intima media thickness (P = 0.039). Furthermore, a significant trend towards increased intima media thickness was observed with increasing numbers of metabolic syndrome components: mean intima media thickness was highest among individuals with all five metabolic syndrome components compared to those with none (866 ± 55 vs 619 ± 23 μm, P = 0.0014). A similar, but non-significant trend was observed for total plaque volume. Conclusion This is the first study of the relationship between the metabolic syndrome and two distinct carotid ultrasound traits measured in the same individuals. The results suggest that standard intima media thickness measurement shows a more consistent and stronger association with the metabolic syndrome than does total plaque volume.

Background and Purpose— Cytosolic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32), encoded by PCK1 , catalyzes the first committed step in gluconeogenesis. We previously showed that a –232C>G promoter polymorphism within a cis -acting element required for basal and cAMP-mediated PCK1 gene transcription results in loss of negative regulation by insulin, contributing to worsened metabolic control in the context of insulin resistance. We hypothesized that this polymorphism would be associated with carotid atherosclerosis in a sample of 150 aboriginal Canadians. Methods— Dependent variables were 2 distinct carotid traits, namely intima-media thickness (IMT) assessed using B-mode ultrasound and total carotid plaque volume (TPV) assessed using 3D ultrasound. Results— Multivariate analysis showed significant but opposite associations of PCK1 genotype with these traits. Specifically, subjects with the PCK1 –232G/G genotype had more carotid IMT (0.80±0.02 versus 0.73±0.03 mm; P =0.007) but less TPV (0.10±0.09 versus 0.38±0.13; P =0.03) than subjects with other genotypes. Conclusions— The findings connect the key enzyme in gluconeogenesis with atherosclerosis. The meaning of the opposing associations of PCK1 genotype with IMT and TPV is unclear; more work is required to confirm whether these might be distinct quantitative traits with different biological determinants.

Background In a recent report of large-scale association analysis, a type 2 diabetes susceptibility locus near HNF1A was identified in predominantly European descent populations. A population-specific G319S polymorphism in HNF1A was previously identified in Aboriginal Canadians who have a high prevalence of type 2 diabetes. We aimed to investigate the association of the HNF1A G319S polymorphism with incident type 2 diabetes and to assess whether clinical risk variables for type 2 diabetes influence the association in an Aboriginal population. Methods Of 606 participants who were free of diabetes at baseline in 1993-1995, 540 (89.1%) participated in 10-year follow-up assessments in 2003-2005. Fasting glucose and a 75-g oral glucose tolerance test were obtained to determine incident type 2 diabetes. Participants were genotyped for the HNF1A G319S polymorphism. Interviewers administered questionnaires on smoking behavior. Results The incidence rates of type 2 diabetes were 14.2% (55/388) in major allele homozygotes and 31.2% (29/93) in minor allele carriers (p < 0.001). The HNF1A G319S carrier status was associated with incident type 2 diabetes (odds ratio [OR] 3.78 [95% CI 2.13-6.69]) after adjustment for age, sex, hypertension, triglyceride, HDL cholesterol, and waist circumference. A statistical interaction was observed between HNF1A G319S and baseline active cigarette smoking on the development of type 2 diabetes with similar adjustment (p = 0.006). When participants were stratified by baseline smoking status, HNF1A G319S carriers who were active smokers had increased risk of developing diabetes (OR 6.91 [95% CI 3.38-14.12]), while the association was attenuated to non-significance among non-smokers (1.11 [0.40-3.08]). Conclusions The HNF1A G319S variant is associated with incident type 2 diabetes in Aboriginal Canadians. Furthermore, cigarette smoking appears to amplify incident diabetes risk in carriers of HNF1A G319S.