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.

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.

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 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.

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.

Maternal pregravid weight is the primary determinant of serum leptin and its metabolic associations in pregnancy, irrespective of gestational glucose tolerance status.

CONTEXT: Several previous studies have investigated circulating levels of the adipokine leptin in relation to gestational diabetes mellitus (GDM). However, these studies have yielded markedly conflicting results, including increased, decreased, and unchanged leptin levels in women with GDM as compared with their peers. OBJECTIVE: We sought to evaluate the metabolic determinants of serum leptin in a well-characterized cohort reflecting the full spectrum of glucose intolerance in pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Metabolic characterization, including oral glucose tolerance test (OGTT) and measurement of serum leptin, insulin, lipids, adiponectin, and C-reactive protein, was performed in 817 pregnant women. The OGTT identified 198 women with GDM, 142 with gestational impaired glucose tolerance, and 477 with normal glucose tolerance. RESULTS: Median leptin (ng/ml) did not differ between the normal glucose tolerance (33.7), gestational impaired glucose tolerance (36.3), and GDM (36.4) groups (P = 0.085). On univariate correlation analysis, leptin was most strongly associated with prepregnancy body mass index (BMI) (r = 0.54, P < 0.0001), fasting insulin (r = 0.60, P < 0.0001), and C-reactive protein (r = 0.38, P < 0.0001) but only weakly associated with area under the glucose curve (AUC(glucose)) on the OGTT (r = 0.10, P = 0.0066). On multiple linear regression analysis, the strongest independent determinant of leptin was prepregnancy BMI (t = 11.55, P < 0.0001), whereas AUC(glucose) was not a significant predictor (t = -0.95, P = 0.34). Furthermore, although its respective associations with fasting insulin, triglycerides, and adiponectin varied across tertiles of prepregnancy BMI, leptin was not significantly associated with AUC(glucose) in any BMI tertile. CONCLUSIONS: Pregravid BMI, rather than gestational glucose tolerance, is the primary determinant of serum leptin concentration in pregnancy.

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.

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.

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.

Role of the fractalkine receptor CX3CR1 polymorphisms V249I and T280M as risk factors for early-onset coronary artery disease in patients with no classic risk factors.

OBJECTIVES: CX3CR1 is a monocyte chemokine receptor and adhesion molecule. Two CX3CR1 mutations, V249I and T280M, reportedly decrease coronary artery disease (CAD) risk independent of established risk factors. An I249 protective effect is attributed to reducing CX3CR1 binding to fractalkine, its ligand. MATERIAL AND METHODS: We examined the frequencies of V249I and T280M among early-onset CAD patients (G1; n = 149; <50 years), late-onset CAD patients (G2; n = 150; >65 years) and healthy controls (HC; n = 149, 47-93 years) without known CAD risk factors. We compared plasma total cholesterol (TC)/high density lipoprotein-C (HDL-C) and apolipoprotein B (APOB)/apolipoprotein AI (APOAI) ratios among the groups and mutation carriers and non-carriers, and the prevalence of the mutations in G1 and G2 patients with multiple coronary vessel disease (MVD) and myocardial infarction (MI). RESULTS: G1 patients had non-significantly lower frequencies of I249 versus (vs.) G2 or controls (G1; 51 %, G2: 61 %, controls: 58 %, p = 0.19), with no difference in T280M (p = 0.8). TC/HDL-C and APOB/APOAI ratios were significantly higher in G1 patients vs. G2 and controls (p<0.0001) independently of either mutation. More G2 patients had MVD than younger ones (p<0.0001); however, more G1 patients were homozygous for V249 compared to G2 patients, who more often had the I249 allele (p<0.02). There was no such association with T280M (p = 0.38). Although more G1 patients had MI, this was not mutation related. CONCLUSIONS: There were significantly higher lipid ratios in G1 compared to G2 and HC (G1>G2>HC), but not in mutation prevalence. I249 mutation was associated with MVD in older patients, while V249 homozygosity was associated with the early-onset CAD. Neither allele affected MI or lipid levels.

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.

Decreased high-molecular-weight adiponectin in gestational diabetes: implications for the pathophysiology of Type 2 diabetes.

AIMS: Low serum concentrations of the insulin-sensitizing protein adiponectin predict the development of incident Type 2 diabetes (T2DM). It has recently emerged that the anti-diabetic activity of adiponectin may be mediated by its high-molecular-weight (HMW) isoform, circulating levels of which are decreased in T2DM. The relevance of decreased HMW adiponectin to incident T2DM, however, has not been assessed. Since gestational diabetes (GDM) identifies a population of young women at high risk of future T2DM (i.e. representing an early stage in the natural history of the disease), we sought to determine if decreased HMW adiponectin is a feature of GDM. METHODS: HMW and total adiponectin were measured in 121 women at the time of oral glucose tolerance testing (OGTT) in late pregnancy, following an abnormal glucose challenge test. Based on the OGTT, there were 41 women with and 80 without GDM. RESULTS: Median HMW adiponectin concentration was lower in women with GDM (3.5 microg/ml) than in those without GDM (5.5 microg/ml) (P < 0.0001). After full adjustment for covariates, mean HMW adiponectin remained significantly lower in women with GDM compared with their peers (3.6 vs. 5.3 microg/ml, P = 0.0035). HMW adiponectin was positively associated with insulin sensitivity (IS(OGTT)) (r = 0.38, P < 0.0001) and pancreatic B-cell function [insulin secretion-sensitivity index (ISSI)] (r = 0.33, P = 0.0002) and inversely related to blood glucose levels, including area-under-the-glucose-curve during the OGTT (AUC(glucose)) (r = -0.31, P = 0.0007). On separate multiple linear regression analyses, HMW adiponectin emerged as an independent determinant of AUC(glucose), IS(OGTT) and ISSI, respectively, mirroring the relationships of total adiponectin. CONCLUSIONS: HMW adiponectin is significantly decreased in women with GDM. Deficiency of HMW adiponectin may be an early event in the natural history of T2DM.

Elevated C-reactive protein in Native Canadian children: an ominous early complication of childhood obesity.

AIM: Subclinical inflammation has been proposed as a pathophysiologic mechanism linking obesity with vascular and metabolic disease. Native North American populations are experiencing high prevalence rates of both (i) childhood obesity and (ii) adult cardiovascular disease (CVD) and type 2 diabetes. Thus, we sought to determine whether subclinical inflammation is an early complication of obesity in Native children. METHODS: Serum concentrations of the inflammatory biomarker C-reactive protein (CRP) were assessed in a population-based, cross-sectional study of the Sandy Lake Oji-Cree community of Northern Ontario, Canada, involving 228 children aged 10-19 years (mean age 14.8). RESULTS: Median CRP in this population was 0.5 mg/l (interquartile range 0.18-1.79 mg/l). CRP levels were higher than age-matched reference data from the Third National Health and Nutrition Examination Survey (NHANES III). Importantly, fully 15.8% of the children of this community had CRP concentrations between 3 and 10 mg/l, a range that identifies adults at high risk of CVD. Moreover, increasing CRP concentration in this paediatric population was associated with an enhanced CV risk profile, consisting of increased adiposity, higher insulin resistance, worsening lipid profile (higher total cholesterol, triglycerides, low-density lipoprotein cholesterol, apolipoprotein B and total cholesterol : high-density-lipoprotein cholesterol ratio), increased leptin and decreased adiponectin. On multivariate analysis, waist circumference and interleukin-6 (IL-6) emerged as independent determinants of CRP concentration. CONCLUSION: Subclinical inflammation is an early complication of childhood obesity in Native children and may foreshadow an increased burden of CVD and type 2 diabetes in the future.

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.

Adiponectin and beta cell dysfunction in gestational diabetes: pathophysiological implications.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) identifies a population of young women at high risk of developing type 2 diabetes and thus provides an excellent model for studying early events in the natural history of this disease. Adiponectin, a novel adipocyte-derived protein with insulin-sensitising properties, has been proposed as a factor linking insulin resistance and beta cell dysfunction in the pathogenesis of type 2 diabetes. We conducted the current investigation to determine whether adiponectin is associated with beta cell dysfunction in GDM. METHODS: We studied 180 women undergoing OGTT in late pregnancy. Based on the OGTT results, participants were stratified into three groups: (1) NGT (n=93); (2) IGT (n=39); and (3) GDM (n=48). First-phase insulin secretion was determined using a validated index previously proposed by Stumvoll. Insulin sensitivity was assessed using the validated OGTT insulin sensitivity index of Matsuda and DeFronzo (IS(OGTT)). RESULTS: To evaluate beta cell function in relation to ambient insulin sensitivity, an insulin secretion-sensitivity index (ISSI) was derived from the product of the Stumvoll index and the IS(OGTT), based on the existence of the predicted hyperbolic relationship between these two measures. Mean ISSI was highest in the NGT group (6,731), followed by that in the IGT group (4,976) and then that in the GDM group (3,300) (overall p<0.0001), compatible with the notion of declining beta cell function across these glucose tolerance groups. Importantly, adiponectin was significantly correlated with ISSI (r=0.34, p<0.0001), with a stepwise increase in mean ISSI observed per tertile of adiponectin concentration (trend p<0.0001). In multivariate linear regression analysis, ISSI was positively correlated with adiponectin and negatively correlated with GDM, IGT and C-reactive protein (r(2)=0.54). CONCLUSIONS/INTERPRETATION: Adiponectin concentration is an independent correlate of beta cell function in late pregnancy. As such, adiponectin may play a key role in mediating insulin resistance and beta cell dysfunction in the pathogenesis of diabetes.

Hypoadiponectinaemia in South Asian women during pregnancy: evidence of ethnic variation in adiponectin concentration.

AIMS: People of South Asian descent face an increased risk of Type 2 diabetes mellitus (DM) and coronary artery disease (CAD) compared with other ethnic groups. One candidate factor underlying this risk may be adiponectin, as circulating levels of this adipocyte-derived protein are reduced in both Type 2 DM and CAD. In a recent study, we assessed the relationship between adiponectin and gestational diabetes (GDM), a potential model of early events in the natural history of Type 2 DM. Here, we report the impact of ethnicity on plasma adiponectin concentration in that study. METHODS: A cross-sectional study was performed in 180 women undergoing oral glucose tolerance testing in late second or early third trimester to investigate the relationship between adiponectin and glucose tolerance in pregnancy. Based on self-reported ethnicity, participants were stratified into three groups: (i) Caucasian (n = 116), (ii) South Asian (n = 31), and (iii) Asian (n = 28). RESULTS: Median adiponectin concentration was much lower in the South Asian group (9.7 micro g/ml) than in Caucasians (15.8 micro g/ml) or Asians (16.1 micro g/ml) (overall P < 0.0001). With adjustment for age, prepregnancy body mass index, weight gain in pregnancy, previous history of GDM, family history of DM, fasting insulin and glucose intolerance, mean adiponectin remained significantly lower among South Asians compared with either Caucasians (P < 0.0001) or Asians (P = 0.0034). CONCLUSIONS: Women of South Asian descent exhibit significantly reduced plasma concentrations of adiponectin in pregnancy compared with Caucasian and Asian counterparts. This observation raises the possibility of hypoadiponectinaemia as a potential factor contributing to the increased risk of diabetes and cardiovascular disease in South Asians.

Relation of waist circumference and glycemic status to C-reactive protein in the Sandy Lake Oji-Cree.

OBJECTIVE: To determine the prevalence of elevated C-reactive protein (CRP) in the Sandy Lake Oji-Cree, an aboriginal community residing in the Sioux Lookout zone of Northwestern Ontario, Canada, and to determine the associations of obesity and diabetes with CRP in a community with a very high prevalence of type II diabetes. DESIGN: We surveyed 512 community members aged 18 y and older to determine the prevalence and the determinants of elevated CRP in Sandy Lake. MEASUREMENTS: Clinical variables, indices of obesity and serum concentrations of CRP, insulin, serum amyloid A (SAA) and interleukin-6 (IL-6). RESULTS: The prevalence of CRP >or=3.8 mg/l was significantly higher in women than in men (51% vs. 32%, P<0.0001). Regression analysis determined that body mass index and IL-6 were independent determinants of CRP concentration in women and waist circumference and IL-6 were independent determinants of CRP concentration in men. Diabetes was associated with elevated CRP in both sexes, but was only a moderate strong determinant in CRP concentration in multivariate regression analysis. CONCLUSIONS: The prevalence of elevated CRP in this aboriginal community is remarkably high. These data further demonstrate that the association between CRP and specific indices of obesity and metabolism vary according to gender and glycemic status.