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Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.
Haydar, S, Grigorescu, F, Vintilă, M, Cogne, Y, Lautier, C, Tutuncu, Y, Brun, JF, Robine, JM, Pugeat, M, Normand, C, et al
PloS one. 2019;(3):e0214122
Abstract
Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.
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Williams-beuren syndrome is a genetic disorder associated with impaired glucose tolerance and diabetes in childhood and adolescence: new insights from a longitudinal study.
Stagi, S, Lapi, E, Cecchi, C, Chiarelli, F, D'Avanzo, MG, Seminara, S, de Martino, M
Hormone research in paediatrics. 2014;(1):38-43
Abstract
BACKGROUND In adults with Williams-Beuren syndrome (WBS), a common endocrine abnormality is type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). However, few and sporadic data are available in children, adolescents, and young adults with WBS. AIM: To evaluate the frequency of IGT and T2DM in a cohort of children and young patients with WBS. PATIENTS AND METHODS We longitudinally evaluated 27 patients (9 males and 18 females, median age at study onset 13.6 years) with WBS. The median follow-up was 3.6 years. Variables of insulin resistance and β-cell function were evaluated in all subjects using an oral glucose tolerance test. The homeostasis model assessment (HOMA) of insulin resistance and the Matsuda index of insulin sensitivity were calculated. The study of the GCK and HNF1Α genes was performed in patients with glucose metabolism abnormalities. 45 age- and sex-matched healthy subjects and 51 age-, sex- and BMI-matched subjects were recruited as two control groups. RESULTS Considering nutritional status, 7 (25.9%) patients were obese, 9 (33.3%) overweight, and 11 (40.8%) normal-weight. One (3.1%) patient had acanthosis nigricans. IGT was diagnosed in 7 (25.9%) WBS patients and T2DM in 3 (11.1%). Considering all WBS patients, the median value of HOMA was 5.23 (range 2.93-14.89; insulin 24.73 ± 14.67 μU/ml; glucose 104.98 ± 16.06 mg/dl). Considering BMI values, HOMA was 11.00 (range 6.53-12.56), 5.64 (range 3.54-7.95), and 4.54 (range 3.21-5.43), and insulin was 34.53 ± 6.84, 22.76 ± 8.91, and 19.47 ± 6.01 μU/ml in obese, overweight, and normal-weight WBS patients, respectively. Comparing the results with the two control groups, WBS patients showed higher insulin values than healthy controls (p < 0.001), but similar values as the BMI-matched control group (p = n.s.). However, WBS patients showed significantly higher values of glycemia (healthy control group, p < 0.001; BMI-matched control group, p < 0.05) and HOMA (healthy control group, p < 0.001; BMI-matched control group, p < 0.05) than the two control groups. Finally, among WBS patients there was a higher number of subjects with IGT and T2DM than among healthy controls (p < 0.0001) and the BMI-matched control group (p = 0.0002). CONCLUSION Our data strongly suggest that IGT and T2DM may be frequently discovered in children, adolescents, and young adults with WBS. WBS should be included among the genetic syndromes associated with T2DM. Further studies are necessary to evaluate the etiopathogenesis of this aspect.
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Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian Diabetes and Exercise Study (IDES).
Balducci, S, Zanuso, S, Nicolucci, A, De Feo, P, Cavallo, S, Cardelli, P, Fallucca, S, Alessi, E, Fallucca, F, Pugliese, G, et al
Archives of internal medicine. 2010;(20):1794-803
Abstract
BACKGROUND This study aimed to assess the efficacy of an intensive exercise intervention strategy in promoting physical activity (PA) and improving hemoglobin A(1c)(HbA(1c)) level and other modifiable cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM). METHODS Of 691 eligible sedentary patients with T2DM and the metabolic syndrome, 606 were enrolled in 22 outpatient diabetes clinics across Italy and randomized by center, age, and diabetes treatment to twice-a-week supervised aerobic and resistance training plus structured exercise counseling (exercise group) vs counseling alone (control group) for 12 months. End points included HbA(1c) level (primary) and other cardiovascular risk factors and coronary heart disease risk scores (secondary). RESULTS The mean (SD) volume of PA (metabolic equivalent hours per week) was significantly higher (P < .001) in the exercise (total PA [nonsupervised conditioning PA + supervised PA], 20.0 [0.9], and nonsupervised, 12.4 [7.4]) vs control (10.0 [8.7]) group. Compared with the control group, supervised exercise produced significant improvements (mean difference [95% confidence interval]) in physical fitness; HbA(1c) level (-0.30% [-0.49% to -0.10%]; P < .001); systolic (-4.2 mm Hg [-6.9 to -1.6 mm Hg]; P = .002) and diastolic (-1.7 mm Hg [-3.3 to -1.1 mm Hg]; P = .03) blood pressure; high-density lipoprotein (3.7 mg/dL [2.2 to 5.3 mg/dL]; P < .001) and low-density lipoprotein (-9.6 mg/dL [-15.9 to -3.3 mg/dL]; P = .003) cholesterol level; waist circumference (-3.6 cm [-4.4 to -2.9 cm]; P < .001); body mass index; insulin resistance; inflammation; and risk scores. These parameters improved only marginally in controls. CONCLUSIONS This exercise intervention strategy was effective in promoting PA and improving HbA(1c) and cardiovascular risk profile. Conversely, counseling alone, though successful in achieving the currently recommended amount of activity, was of limited efficacy on cardiovascular risk factors, suggesting the need for a larger volume of PA in these high-risk subjects. Trial Registration isrctn.org Identifier: ISRCTN04252749.
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Changes in abdominal subcutaneous fat water content with rapid weight loss and long-term weight maintenance in abdominally obese men and women.
Laaksonen, DE, Nuutinen, J, Lahtinen, T, Rissanen, A, Niskanen, LK
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 2003;(6):677-83
Abstract
OBJECTIVE Insulin resistance decreases blood flow and volume in fat tissue. We hypothesised that fat tissue nutritive blood flow and volume, and thereby water content, would increase during weight loss and weight maintenance in obese persons. DESIGN Longitudinal clinical intervention with a 9-week very-low-calorie diet (VLCD) followed by one year of weight maintenance. SUBJECTS Obese men (n=13) and women (n=14) with the metabolic syndrome. MEASUREMENTS Water content of abdominal subcutaneous fat tissue as estimated by a sensor on the skin surface measuring the dielectric constant at 300 MHz. Anthropometric measures of fatness and fat distribution. Biochemical measures related to insulin resistance. RESULTS Subjects lost 14.5+/-3.4% of body weight during the VLCD, and generally sustained this weight loss during weight maintenance. Insulin sensitivity as estimated by an index (qualitative insulin sensitivity check index) increased during the VLCD, and remained increased throughout weight maintenance. The dielectric constant increased from 23.3+/-2.3 to 25.0+/-2.1 (P<0.001) during the VLCD, and further to 27.8+/-1.9 (P<0.001) during weight maintenance, indicating an increase in the water content of subcutaneous fat. The increase in subcutaneous fat water content did not correlate with weight loss and other measures of adiposity during the VLCD, but there was an inverse correlation that strengthened in significance from baseline to 6, 9 and 12 mo (r=-0.32 to -0.64, P=0.079-0.002). Increases in subcutaneous fat water content also correlated with improvements in insulin sensitivity at 6, 9 and 12 months of weight maintenance (r=0.34-0.54, P=0.094-0.006). CONCLUSIONS Water content of abdominal subcutaneous adipose tissue increases with weight loss in obese persons with the metabolic syndrome, and may reflect increased subcutaneous fat tissue nutritive blood flow. The increase in water content correlates with the increase in insulin sensitivity, suggesting that weight loss and consequent improved insulin sensitivity could mediate the increase in abdominal subcutaneous fat hydration.