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1.
The relationship of insulin resistance estimated by triglyceride glucose index and coronary plaque characteristics.
Won, KB, Kim, YS, Lee, BK, Heo, R, Han, D, Lee, JH, Lee, SE, Sung, JM, Cho, I, Park, HB, et al
Medicine. 2018;(21):e10726
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Abstract
The triglyceride glucose (TyG) index is a useful surrogate marker for insulin resistance, which is an important risk factor for coronary artery disease (CAD). However, data on the relationship of the TyG index and coronary plaque characteristics are limited.This study included 2840 participants with near-normal renal function who underwent coronary computed tomography angiography. CAD was defined as the presence of any plaques, and obstructive CAD was defined as the presence of plaques with ≥50% stenosis. The relationship between the TyG index and noncalcified plaque (NCP), calcified or mixed plaque (CMP), and coronary artery calcium score (CACS) was evaluated.All participants were stratified into 4 groups based on the quartiles of the TyG index. The prevalence of CAD and obstructive CAD significantly increased with increasing quartiles. The risk for NCP and obstructive NCP was not different among all groups. However, compared with group I (lowest quartile), the risk for CMP was higher in groups III (odds ratio [OR]: 1.438) and IV (highest quartile) (OR: 1.895) (P < .05), and that for obstructive CMP was higher in groups II (OR: 1.469), III (OR: 1.595), and IV (OR: 2.168) (P < .05). Multivariate regression analysis showed that the TyG index was associated with an increased risk for CAD (OR: 1.700), obstructive CAD (OR: 1.692), and CACS >400 (OR: 1.448) (P < .05).The TyG index was independently associated with the presence and severity of CAD due to an increased risk for CMP.
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Interrelationship between diabetes mellitus and heart failure: the role of peroxisome proliferator-activated receptors in left ventricle performance.
Oikonomou, E, Mourouzis, K, Fountoulakis, P, Papamikroulis, GA, Siasos, G, Antonopoulos, A, Vogiatzi, G, Tsalamadris, S, Vavuranakis, M, Tousoulis, D
Heart failure reviews. 2018;(3):389-408
Abstract
Heart failure (HF) is a common cardiac syndrome, whose pathophysiology involves complex mechanisms, some of which remain unknown. Diabetes mellitus (DM) constitutes not only a glucose metabolic disorder accompanied by insulin resistance but also a risk factor for cardiovascular disease and HF. During the last years though emerging data set up, a bidirectional interrelationship between these two entities. In the case of DM impaired calcium homeostasis, free fatty acid metabolism, redox state, and advance glycation end products may accelerate cardiac dysfunction. On the other hand, when HF exists, hypoperfusion of the liver and pancreas, b-blocker and diuretic treatment, and autonomic nervous system dysfunction may cause impairment of glucose metabolism. These molecular pathways may be used as therapeutic targets for novel antidiabetic agents. Peroxisome proliferator-activated receptors (PPARs) not only improve insulin resistance and glucose and lipid metabolism but also manifest a diversity of actions directly or indirectly associated with systolic or diastolic performance of left ventricle and symptoms of HF. Interestingly, they may beneficially affect remodeling of the left ventricle, fibrosis, and diastolic performance but they may cause impaired water handing, sodium retention, and decompensation of HF which should be taken into consideration in the management of patients with DM. In this review article, we present the pathophysiological data linking HF with DM and we focus on the molecular mechanisms of PPARs agonists in left ventricle systolic and diastolic performance providing useful insights in the molecular mechanism of this class of metabolically active regiments.
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Insulin resistance and glycine metabolism in humans.
Adeva-Andany, M, Souto-Adeva, G, Ameneiros-Rodríguez, E, Fernández-Fernández, C, Donapetry-García, C, Domínguez-Montero, A
Amino acids. 2018;(1):11-27
Abstract
Plasma glycine level is low in patients with obesity or diabetes and the improvement of insulin resistance increases plasma glycine concentration. In prospective studies, hypoglycinemia at baseline predicts the risk of developing type 2 diabetes and higher serum glycine level is associated with decreased risk of incident type 2 diabetes. Consistently, plasma glycine concentration is lower in the lean offspring of parents with type 2 diabetes compared to healthy subjects. Among patients with type 2 diabetes, hypoglycinemia occurs before clinical manifestations of the disease, but the pathophysiological mechanisms underlying glycine deficit and its potential clinical repercussions are unclear. Glycine participates in several metabolic pathways, being required for relevant human physiological processes. Humans synthesize glycine from glyoxylate, glucose (via serine), betaine and likely from threonine and during the endogenous synthesis of L-carnitine. Glycine conjugates bile acids and other acyl moieties producing acyl-glycine derivatives. The glycine cleavage system catalyzes glycine degradation to carbon dioxide and ammonium while tetrahydrofolate is converted into 5,10-methylene-tetrahydrofolate. Glycine is utilized to synthesize serine, sarcosine, purines, creatine, heme group, glutathione, and collagen. Glycine is a major quantitative component of collagen. In addition, the role of glycine maintaining collagen structure is critical, as glycine residues are required to stabilize the triple helix of the collagen molecule. This quality of glycine likely contributes to explain the occurrence of medial arterial calcification and the elevated cardiovascular risk associated with diabetes and chronic kidney disease, as emerging evidence links normal collagen content with the initiation and progression of vascular calcification in humans.
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Body composition and insulin resistance in children.
Maffeis, C, Morandi, A
European journal of clinical nutrition. 2018;(9):1239-1245
Abstract
Insulin resistance is a condition of gluco-metabolic sufferance that may hesitate in the further development of type 2 diabetes and cardiovascular disease. The development of insulin resistance is mostly associated with the accumulation of excessive fat in the body. The epidemic impact of obesity in the youngest promoted an increase of the prevalence of insulin resistance also in children and adolescents. Increased fat accumulation in the peri-visceral area of the abdomen, occurring preferably at and after puberty, and in the liver, as non-alcoholic fatty liver disease, plays a role in the process. After puberty, males are at higher risk than females to develop insulin resistance. Also ethnicity contributes to sensitivity of children to develop insulin resistance, where Hispanics, South-Asians, and Indians are at higher risk than Whites and Blacks.In spite of the research progress in the field, several questions on the relationship between body composition and insulin resistance are still unanswered. Multiomics approach, combined with nutrition as well as imaging techniques might contribute to unravel the role of body composition on insulin resistance.
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The anorexigenic peptide neurotensin relates to insulin sensitivity in obese patients after BPD or RYGB metabolic surgery.
von Loeffelholz, C, Gissey, LC, Schumann, T, Henke, C, Kurzbach, A, Struck, J, Bergmann, A, Hanefeld, M, Schatz, U, Bornstein, SR, et al
International journal of obesity (2005). 2018;(12):2057-2061
Abstract
Neurotensin is a peptide with effects on appetite and intestinal lipid absorption. Experimental data suggest a role in glucose homeostasis, while human data is missing. Here, 20 morbidly obese subjects either underwent biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB) in a randomized fashion. Before and 1 year after surgery, anthropometric data, body composition, clinical biochemistry, insulin sensitivity by means of euglycemic hyperinsulinemic clamps (HEC) and fasting plasma proneurotensin 1-117 were analyzed. Plasma proneurotensin increased significantly more 1 year after BDP than RYGB (P = 0.028), while weight loss was comparable. After metabolic surgery, proneurotensin correlated positively with insulin sensitivity (M-value) (r = 0.55, P < 0.001), while an inverse relationship with fasting glucose, HOMA-IR and HbA1c was observed (P < 0.05 for all components). After adjustment for age and gender, proneurotensin and BMI remained independently related with delta of M-value (β = 0.46 and β = 0.51, P < 0.05, resp.). From these data we conclude that proneurotensin positively correlates with insulin sensitivity uniquely after weight loss induced by metabolic surgery in humans. BDP leads to a stronger increase in the anorexigenic peptide compared to RYGB.
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The association of SNP276G>T at adiponectin gene with insulin resistance and circulating adiponectin in response to two different hypocaloric diets.
de Luis, DA, Izaola, O, Primo, D, Aller, R, Ortola, A, Gómez, E, Lopez, JJ
Diabetes research and clinical practice. 2018;:93-99
Abstract
BACKGROUND Several adiponectin gene (ADIPOQ) single nucleotide polymorphisms (SNPS) have been related with adiponectin levels and risk for obesity. OBJECTIVE The aim of our study was to analyze the effect of rs1501299 ADIPOQ gene polymorphism and dietary intake on total adiponectin levels and insulin resistance after two hypocaloric diets in obese subjects. MATERIAL AND METHODS A Caucasian population of 284 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (I: moderate carbohydrates vs II: low fat). Before and after 12 weeks on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were realized. The statistical analysis was performed for the combined GT and TT as a group (mutant) and GG as second group (wild) (dominant model). RESULTS The genotype distribution was 149 GG, 124 GT and 21 TT. With caloric restriction strategies, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, total LDL cholesterol, LDL cholesterol and leptin levels decreased. Only in subjects with GG genotype, diet I and II decreased fasting insulin levels, HOMA-IR and adiponectin levels. The improvement was similar with both diets; insulin concentrations (Diet I: -4.7 ± 1.4 mUI/L vs. Diet II: -5.9 ± 1.9 mUI/L: p = .76), HOMA-IR (Diet I: -1.4 ± 0.6 units vs. Diet II: -2.0 ± 0.7 units: p = .56) and adiponectin levels (Diet I: -10.2 ± 3.4 ng/dl vs. Diet II: -14.0 ± 2.9 ng/dl: p = .33). CONCLUSION The GG genotype of ADIPOQ gene variant (rs1501299) is associated with an increase in adiponectin levels and a decrease of insulin and HOMA-IR after weight loss.
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Performance of individually measured vs population-based C-peptide kinetics to assess β-cell function in the presence and absence of acute insulin resistance.
Varghese, RT, Dalla Man, C, Laurenti, MC, Piccinini, F, Sharma, A, Shah, M, Bailey, KR, Rizza, RA, Cobelli, C, Vella, A
Diabetes, obesity & metabolism. 2018;(3):549-555
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Abstract
AIMS: To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate β-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where β-cell function is measured. METHODS Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS These data support the use of population-based measures of C-peptide kinetics to estimate β-cell function during an OGTT.
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Effects of 6 vs 3 eucaloric meal patterns on glycaemic control and satiety in people with impaired glucose tolerance or overt type 2 diabetes: A randomized trial.
Papakonstantinou, E, Kontogianni, MD, Mitrou, P, Magriplis, E, Vassiliadi, D, Nomikos, T, Lambadiari, V, Georgousopoulou, E, Dimitriadis, G
Diabetes & metabolism. 2018;(3):226-234
Abstract
BACKGROUND/OBJECTIVES The study aimed to compare the effects of two eucaloric meal patterns (3 vs 6 meals/day) on glycaemic control and satiety in subjects with impaired glucose tolerance and plasma glucose (PG) levels 140-199mg/dL at 120min (IGT-A) or PG levels 140-199mg/dL at 120min and >200mg/dL at 30/60/90min post-oral glucose load on 75-g OGTT (IGT-B), or overt treatment-naïve type 2 diabetes (T2D). SUBJECTS/METHODS In this randomized crossover study, subjects with IGT-A (n=15, BMI: 32.4±5.2kg/m2), IGT-B (n=20, BMI: 32.5±5kg/m2) or T2D (n=12, BMI: 32.2±5.2kg/m2) followed a weight-maintenance diet (45% carbohydrates, 20% proteins, 35% fats) in 3 or 6 meals/day (each intervention lasting 12 weeks). Anthropometrics, diet compliance and subjective appetite were assessed every 2 weeks. OGTT and measurements of HbA1c and plasma lipids were performed at the beginning and end of each intervention period. RESULTS Body weight and physical activity levels remained stable throughout the study. In T2D, HbA1c and PG at 120min post-OGTT decreased with 6 vs 3 meals (P<0.001 vs P=0.02, respectively). The 6-meal intervention also improved post-OGTT hyperinsulinaemia in IGT-A subjects and hyperglycaemia in IGT-B subjects. In all three groups, subjective hunger and desire to eat were reduced with 6 vs 3 meals/day (P<0.05). There were no differences in HOMA-IR or plasma lipids between interventions. CONCLUSION Although weight loss remains the key strategy in hyperglycaemia management, dietary measures such as more frequent and smaller meals may be helpful for those not sufficiently motivated to adhere to calorie-restricted diets. Our study shows that 6 vs 3 meals a day can increase glycaemic control in obese patients with early-stage T2D, and may perhaps improve and/or stabilize postprandial glucose regulation in prediabetes subjects.
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[Effects of oral vitamin D3 supplementation in stage 3 chronic kidney disease subjects: insulin resistance syndrome and hormonal disturb interactions].
Tahar, A, Zerdoumi, F, Saidani, M, Griene, L, Koceir, EA
Annales de biologie clinique. 2018;(3):313-325
Abstract
The 1-25-hydroxyvitamine D (1-25OHD) or calcitriol deficiency in chronic kidney disease (CKD) patients was associated with increases vascular calcification risk, nephrons reduction, bone deficit and cardiovascular mortality by atherosclerosis. The objective of this study was to investigate the pleiotropic effects of 200.000 IU (D200 group) every 3 months versus 30.000 IU (D30 group) every month dose vitamin D supplementation in stage 3 CKD patients. A cohort of 132 adult subjects was randomized into 2 groups according to dose vitamin D supplementation in deficient subjects (25OHD <50 nmol/L or <20 ng/mL). Serum 25OHD levels were assessed before and after 6 and 12 months of vitamin D supplementation. Patients were phenotyped for IRS according to NCEP/ATPIII. Glomerular filtration rate (GFR) by the MDRD formula. Insulin resistance was evaluated by the Homa-IR model. IRS clusters by Cobas Integra 400®. PTH, Cortisol and IGF-1 were determined by radioimmunologic methods. The 25OHD profile was analyzed by LC-MS/MS. Results showed that vitamin D supplementation increased serum 25OHD concentrations (>75 nmol/L or >30 ng/mL) in both groups; however, the supplementation benefits are more significant in D30 group than in D200 group. We noted a highlighted improvement of kidney function, an inhibition of GFR collaps, a safe reduction of proteinuria, a significant PTH and C-reactive protein (inflammation) levels attenuation, concomitantly with cortisolemia normalization and decreased IGF-1 depletion. Nevertheless, homocysteine and Lp(a) concentrations remain increased, not modulated by vitamin D treatment. This study shows that continuous low doses (30.000 IU every month) are recommended for intermittent high doses (200.000 IU every 3 months) vitamin D supplementation. Our study suggests that the serum 25OHD profile can be considered a reliable biomarker in the bioclinic CKD status to stage stabilization and inhibit its evolution.
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Chronic kidney disease attenuates the plasma metabolome response to insulin.
Roshanravan, B, Zelnick, LR, Djucovic, D, Gu, H, Alvarez, JA, Ziegler, TR, Gamboa, JL, Utzschneider, K, Kestenbaum, B, Himmelfarb, J, et al
JCI insight. 2018;(16)
Abstract
Chronic kidney disease (CKD) leads to decreased sensitivity to the metabolic effects of insulin, contributing to protein energy wasting and muscle atrophy. Targeted metabolomics profiling during hyperinsulinemic-euglycemic insulin clamp testing may help identify aberrant metabolic pathways contributing to insulin resistance in CKD. Using targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with CKD, 37 with normal glomerular filtration rate [GFR]) who underwent hyperinsulinemic-euglycemic clamp. We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential metabolic pathways linking CKD with insulin resistance. Baseline differences and effect modification by CKD status on changes with insulin clamp testing were adjusted for confounders. Mean GFR among participants with CKD was 37.3 compared with 89.3 ml/min per 1.73 m2 among controls. Fasted-state differences between CKD and controls included abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle. Insulin infusion markedly decreased metabolite levels, predominantly amino acids and their metabolites. CKD was associated with attenuated insulin-induced changes in nicotinamide, arachidonic acid, and glutamine/glutamate metabolic pathways. Metabolomics profiling suggests disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.