Publications by authors named "Luis E Simental-Mendia"

122 Publications

Antidiabetic Properties of Curcumin: Insights on New Mechanisms.

Adv Exp Med Biol 2021 ;1291:151-164

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Plant extracts have been used to treat a wide range of human diseases. Curcumin, a bioactive polyphenol derived from Curcuma longa L., exhibits therapeutic effects against diabetes while only negligible adverse effects have been observed. Antioxidant and anti-inflammatory properties of curcumin are the main and well-recognized pharmacological effects that might explain its antidiabetic effects. Additionally, curcumin may regulate novel signaling molecules and enzymes involved in the pathophysiology of diabetes, including glucagon-like peptide-1, dipeptidyl peptidase-4, glucose transporters, alpha-glycosidase, alpha-amylase, and peroxisome proliferator-activated receptor gamma (PPARγ). Recent findings from in vitro and in vivo studies on novel signaling pathways involved in the potential beneficial effects of curcumin for the treatment of diabetes are discussed in this review.
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http://dx.doi.org/10.1007/978-3-030-56153-6_9DOI Listing
January 2021

Impact of Bariatric Surgery on Pulse Wave Velocity as a Measure of Arterial Stiffness: a Systematic Review and Meta-analysis.

Obes Surg 2021 Jul 28. Epub 2021 Jul 28.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Purpose: Weight loss during post-bariatric surgery period has been linked to both reduced ASCVD mortality and overall mortality. Atherosclerosis causes arteries to lose their elasticity and become more stiff resulting in increased pulse wave velocity (PWV). It has been revealed that PWV favorably predicts subsequent ASCVDs. The goal of this systematic review and meta-analysis was to see how bariatric surgery affected PWV, an index of arterial stiffness.

Materials And Methods: A systematic literature search in four databases was performed. Also, Cochrane guidelines were reviewed to determine bias possibility in the related studies. Comprehensive Meta-Analysis (CMA) V2 software is used to conduct the meta-analysis. Studies were evaluated regarding heterogeneity in design, populations under investigation, and treatment duration using random-effects model and the generic inverse variance weighting approach. A random-effect meta-regression approach was used to investigate the association with the estimated effect size. Evaluation of funnel plot, Egger's weighted regression, and Begg's rank correlation tests were utilized to estimate the presence of publication bias in the meta-analysis.

Results: The results of meta-analysis on 13 trials including 1426 individuals demonstrated a remarkable decline of PWV after bariatric surgery (WMD: -0.652, 95% CI: -1.004, -0.301, p<0.001). The random-effects meta-regression revealed no evidence of significant correlation between the changes in PWV and initial BMI, BMI changes, or duration of follow-up.

Conclusion: The decrease of PWV might be utilized as an independent surrogate marker of improvement of ASCVD risk after bariatric surgery.
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http://dx.doi.org/10.1007/s11695-021-05611-7DOI Listing
July 2021

Effect of hydroxychloroquine on lipid levels: A systematic review and meta-analysis.

Curr Pharm Des 2021 Jun 25. Epub 2021 Jun 25.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico.

Background: It has been suggested that hydroxychloroquine may have positive effects on LDL-C, HDL-C, and triglyceride levels; however, the hypolipidemic activities of this drug are still uncertain.

Objective: The aim of this meta-analysis of randomized controlled trials was to explore the effect of hydroxychloroquine on circulating lipid concentrations.

Method: Randomized controlled trials examining the impact of hydroxychloroquine on lipid parameters were searched in PubMed, Web of Science, Scopus, and Google Scholar databases. Meta-analysis was performed using a random-effects model and sensitivity analysis through the leave one-out method.

Results: Meta-analysis showed that patients receiving hydroxychloroquine therapy significantly decreased total cholesterol (WMD: 0.18 mmol/L, 95% CI: -0.28, -0.08, I2 = 6%, p = 0.0004), LDL-C (WMD: -0.21 mmol/L, 95% CI: -0.36, -0.06, I2 = 75%, p = 0.006), triglycerides (WMD: -0.09 mmol/L, 95% CI: -0.15, -0.04, I2 = 22%, p = 0.001), and non-HDL-C (WMD: -0.28 mmol/L, 95% CI: -0.45, -0.12, I2 = 0%, p = 0.0009), and increased HDL-C concentrations (WMD: 0.03 mmol/L, 95% CI: 0.00, 0.06, I2 = 0%, p = 0.03).

Conclusion: Our results suggest that hydroxychloroquine improves lipid parameters by reducing total cholesterol, LDL-C, triglycerides, non-HDL-C, and increasing HDL-C levels.
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http://dx.doi.org/10.2174/1381612827666210625162612DOI Listing
June 2021

The role of incretins and incretin-based drugs in autoimmune diseases.

Int Immunopharmacol 2021 Jun 11;98:107845. Epub 2021 Jun 11.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Incretin hormones, including glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP), are gastrointestinal peptides secreted from enteroendocrine cells. These hormones play significant roles in many physiological processes via binding to G-protein coupled receptors (GPCRs) on different organs and tissues; one of them is the immunomodulatory effect on the immune system and its molecular components such as cytokines and chemokines. Anti-inflammatory effects of incretins and dependent molecules involving long-acting analogs and DPP4 inhibitors through regulation of T and B cell activation may attenuate autoimmune diseases caused by immune system disorders in mistakenly recognizing self as the foreign agent. In this review, we investigate incretin effects on the immune system response and the potential benefits of incretin-based therapy for treating autoimmune diseases.
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http://dx.doi.org/10.1016/j.intimp.2021.107845DOI Listing
June 2021

Effect of glucagon-like peptide-1 receptor agonists on circulating levels of leptin and resistin: A meta-analysis of randomized controlled trials.

Diabetes Res Clin Pract 2021 Jun 5;177:108899. Epub 2021 Jun 5.

Department of Orthopedics and Traumatology, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico. Electronic address:

Aim: Previous studies have found reduced concentrations of both leptin and resistin after glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment; however, the evidence in this field is inconclusive. Therefore, the aim of this meta-analysis of randomized controlled trials was to evaluate the effect of GLP-1 RA on both leptin and resistin levels.

Methods: The present systematic review and meta-analysis included randomized controlled trials investigating the effect of GLP-1 RA on leptin and resistin concentrations. For this, PubMed-MEDLINE, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases were searched. A random-effects model and a sensitivity analysis were performed for meta-analysis.

Results: Meta-analysis of 13 randomized controlled trials comprising 1,025 subjects indicated that administration of GLP-1 RA significantly decreases leptin (WMD: -4.85 ng/mL, 95% CI: -9.32, -0.38, p = 0.03) and resistin (WMD: -1.40 ng/mL, 95% CI: -2.78, -0.01, p = 0.05) serum levels. However, the effect size was sensitive to four studies for both leptin and resistin concentrations.

Conclusion: The results of this meta-analysis of randomized controlled trials suggest that GLP-1 RA therapy reduces both leptin and resistin levels.
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http://dx.doi.org/10.1016/j.diabres.2021.108899DOI Listing
June 2021

Effect of hydroxychloroquine on glucose control in patients with and without diabetes: a systematic review and meta-analysis of randomized controlled clinical trials.

Eur J Clin Pharmacol 2021 May 19. Epub 2021 May 19.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, Dgo, México.

Purpose: The aim of this meta-analysis of randomized controlled trials was to evaluate the effect of hydroxychloroquine on glucose control.

Methods: Randomized controlled trials examining the impact of hydroxychloroquine on glycemic markers were searched in PubMed, Web of Science, Scopus, and Google Scholar databases. Meta-analysis was performed using a random-effects model and sensitivity analysis through the leave-one-out method.

Results: Meta-analysis revealed a significant reduction of fasting glucose (WMD: - 8.05 mg/dl; 95% CI: - 11.17, - 4.93; I = 75%; p ˂0.0001), 2-h postprandial glucose (WMD: - 15.52 mg/dl; 95% CI: - 20.61, - 10.42; I = 53%; p ˂0.00001), and glycated hemoglobin (HbA1c) values (WMD: - 0.19%, 95% CI: - 0.37, - 0.02; I = 94%; p = 0.03) after hydroxychloroquine treatment. Otherwise, meta-analysis showed no significant effect of hydroxychloroquine on insulin levels (WMD: 16.52 μUI/ml; 95% CI: - 16.35, 49.40; I = 90%; p = 0.32) and HOMA-β (WMD: - 14.62; 95% CI: - 45.84, 16.59; I = 0%; p = 0.36).

Conclusion: The present meta-analysis revealed that treatment with hydroxychloroquine improves glucose control through the reduction of fasting glucose, 2-h postprandial glucose, and HbA1c values. Given that the effect of hydroxychloroquine on beta-cell function is based only on two clinical trials, it is not possible to draw definitive conclusions.
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http://dx.doi.org/10.1007/s00228-021-03144-7DOI Listing
May 2021

Beneficial Effects of Plant-Derived Natural Products on Non-alcoholic Fatty Liver Disease.

Adv Exp Med Biol 2021 ;1308:257-272

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, México.

Non-alcoholic fatty liver disease is becoming in one of the most prevalent liver diseases that leads to liver transplantation. This health problem is a multisystem disease with a complex pathogenesis that involves liver, adipose tissue, gut, and muscle. Although several pharmacological agents have been investigated to prevent or treat non-alcoholic fatty liver disease, currently there is no effective treatment for the management of this chronic liver disease. Nonetheless, the use of natural products has emerged as a alternative therapeutic for the treatment of hepatic diseases, including non-alcoholic fatty liver disease, due to its anti-inflammatory, antioxidant, antidiabetic, insulin-sensitizing, antiobesity, hypolipidemic, and hepatoprotective properties. In the present review, we have discussed the evidence from experimental and clinical studies regarding the potential beneficial effects of plant-derived natural products (quercetin, resveratrol, berberine, pomegranate, curcumin, cinnamon, green tea, coffee, garlic, ginger, ginseng, and gingko biloba) for the treatment or prevention of non-alcoholic fatty liver disease.
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http://dx.doi.org/10.1007/978-3-030-64872-5_18DOI Listing
April 2021

Therapeutic Effect of Curcumin in Women with Polycystic Ovary Syndrome Receiving Metformin: A Randomized Controlled Trial.

Adv Exp Med Biol 2021 ;1308:109-117

Department of Gynecology and Obstetrics, Iran University of Medical Sciences, Tehran, Iran.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, for which the insulin sensitizer metformin has been used therapeutically. It has been shown that curcumin also exhibits insulin-sensitizing properties. Given that metformin acts as an ovulation inducing agent and both curcumin and metformin can reduce insulin resistance, the aim of the current study was to evaluate the effect of metformin with and without curcumin nanomicelles in the treatment of women with polycystic ovary syndrome. This clinical trial was conducted on 100 women with PCOS, diagnosed according to the Rotterdam criteria, who were sequentially recruited and randomly divided into two groups (n = 50 each). Group 1 received 500 mg metformin three times daily and group 2 received 80 mg/day capsule of curcumin nanomicelle and 500 mg metformin three times a day for 3 months. After collecting fasting blood samples, biochemical parameters including triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, plasma glucose, alanine amino transferase (ALT) and aspartate aminotransferase (AST) were evaluated based on enzymatic methods. Hormonal parameters were assessed using immunoassay kits. Insulin resistance (HOMA-IR) and insulin-sensitivity check index (QUICKI) were also assessed. After treatment, fasting insulin, HOMA-IR, and total testosterone in group 2 were significantly lower than those in group 1 (p < 0.05). Post-treatment LDL-C levels in groups 1 and 2 were 117.9 ± 24 and 91.12 ± 19.46 mg/dL, respectively (p < 0.01). In addition, HDL-C levels were increased with curcumin (group 1: 38.1 ± 4.36 mg/dL; group 2: 44.12 ± 7.3 mg/dL, p < 0.05). Total cholesterol was decreased with curcumin level (group 1: 207.9 ± 39.84 mg/dL; group 2; 159.7 ± 48.43 mg/dL, p < 0.05), with a decrease in triglycerides levels (group 1: 141.6 ± 9.57; group 2: 97.5 ± 8.8 mg/dL, p < 0.01). This study showed that curcumin has a synergistic effect with metformin in the improvement of insulin resistance and lipid profile in patients with PCOS. Therefore, the combined use of metformin and curcumin may have therapeutic utility in patients with PCOS.
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http://dx.doi.org/10.1007/978-3-030-64872-5_9DOI Listing
April 2021

Protective Effects of Curcumin Phytosomes Against High-Fat Diet-Induced Atherosclerosis.

Adv Exp Med Biol 2021 ;1308:37-44

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Curcumin has been shown to have beneficial effects on pathogenic factors involved in the development of atherosclerosis. The aim of this study was to assess the effects of curcumin phytosomes on atherosclerosis induced by high-fat diet in rabbits. A total of 16 adult male New Zealand white rabbits (1.8-2 kg) were fed with a diet containing 0.5% cholesterol for 4 weeks. The rabbits were randomly divided into four groups of four animals each. Group I orally received PBS for 4 weeks. Group II animals were treated with curcumin-phosphatidylcholine solid state dispersion (Meriva®, Indena, Italy) suspended in normal saline at doses equivalent to 100 mg/kg of curcuminoids per day p.o., for 4 weeks. Groups III and IV were treated with curcumin-phosphatidylserine solid state dispersion (Meriserin®, Indena, Italy) suspended in normal saline at doses equivalent to 10 and 100 mg/kg of curcuminoids, respectively, per day p.o., for 4 weeks. For atherosclerosis evaluation, histological examinations on aortic arch section were performed. Blood samples were obtained to determine lipid profile and high-sensitivity C-reactive protein (hs-CRP) levels. Curcumin-phosphatidylserine (100 mg/kg) therapy resulted in a significant reduction in grading of atherosclerotic plaque and intima/media thickness ratio (P < 0.05) and decreased presence of inflammatory cells in the atherosclerotic lesions compared to the control group. However, no significant differences were observed between the curcumin-phospholipid preparations and the control group regarding lipid profile and hs-CRP levels. Results of the present study revealed an atheroprotective effect of curcumin-phosphatidylserine (100 mg/kg) solid dispersion as revealed by a reduction in the development of atherosclerotic lesions.
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http://dx.doi.org/10.1007/978-3-030-64872-5_4DOI Listing
April 2021

Impact of glucagon-like peptide-1 receptor agonists on adiponectin concentrations: A meta-analysis of randomized controlled trials.

Br J Clin Pharmacol 2021 Apr 9. Epub 2021 Apr 9.

Universidad Autonoma de Nuevo Leon, Department of Orthopedics and Traumatology, University Hospital "Dr. José E. González", School of Medicine, Monterrey, NL, Mexico.

Aims: Previous studies have reported an elevation in adiponectin concentrations using glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy; however, this possible pleiotropic effect is still uncertain. Thus, the objective of this meta-analysis of randomized controlled trials was to assess the impact of GLP-1 RA on adiponectin levels.

Methods: This systematic review and meta-analysis included randomized controlled trials investigating the effect of GLP-1 RA on circulating adiponectin concentrations. Studies from PubMed, Web of Science, Scopus, and Google Scholar databases were included. A random-effects model and a sensitivity analysis using the leave 1-out method were conducted.

Results: A meta-analysis of 20 randomized controlled trials involving 1497 individuals demonstrated a significant increase in adiponectin levels after GLP-1 RA administration (weighted mean difference [WMD]: 0.59 μg/mL, 95% confidence interval [CI]: 0.10, 1.08, P = .02). Particularly, liraglutide had a significant effect on adiponectin (WMD: 0.55 μg/mL, 95% CI: 0.04, 1.06, P = .04), while exenatide did not affect these concentrations (WMD: 0.60 μg/mL, 95% CI: -0.23, 1.42, P = .16).

Conclusion: GLP-1 RA treatment is associated with an increase in adiponectin levels.
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http://dx.doi.org/10.1111/bcp.14855DOI Listing
April 2021

Hypoglycemic and antioxidant effects of green tomato (Physalis ixocarpa Brot.) calyxes' extracts.

J Food Biochem 2021 04 24;45(4):e13678. Epub 2021 Feb 24.

Unidad de Investigación Biomédica, Instituto Mexicano del Seguro Social, Durango, Mexico.

The aim of this study was to evaluate the hypoglycemic and antioxidant potential of green tomato (Physalis ixocarpa Brot.) calyxes' extracts. Three methods were used to obtain the extracts: maceration (M), ultrasound-assisted (US), and infusion. Regarding in vitro hypoglycemic evaluation, glucose diffusion assay and enzymatic inhibitory action of α-amylase and α-glucosidase were performed. Whereas, for in vivo assessment an oral starch tolerance test (OSTT) was tested with aqueous extracts [infusion (40 mg/kg b. wt.), maceration (M) water (98 mg/kg b. wt.), and US water (82.24 mg/kg b. wt.)] on male Wistar rats. Additionally, in vitro antioxidant activity of P. ixocarpa calyxes' was evaluated through inhibition of scavenging radical assay and lipid peroxidation. Extracts decreased the glucose diffusion in a range of 18%-56% compared with the negative control. Additionally, extracts inhibited α-amylase (above 80%) and α-glucosidase enzymes (above 90%). All groups treated with P. ixocarpa calyxes' significantly reduced the glucose levels at 120 min (infusion = 13.3%, M Water = 12.7%, and US Water = 19.4%) in comparison with the negative control, and similar levels to acarbose at 120 min (13.1%). Finally, extracts showed IC values in a range of 2.5-6.6 µg/µl for radical scavenging, and 118-199 µg/µl for lipid oxidation. Our results show that P. ixocarpa calyxes' extracts induce hypoglycemia and antioxidant effects in vitro and in vivo. PRACTICAL APPLICATIONS: The green tomato is usually consumed in Mexico, the United States, and Central America. This fruit grows inside a calyx, which is considered an agro-food waste. However, some regions of Latin America have a traditional medicine purpose for diabetes affections. To the best of our knowledge, there are no published data that supports its hypoglycemic action. The information provided will be useful to nutraceutical applications that allow value-added products and sustainable green tomato production.
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http://dx.doi.org/10.1111/jfbc.13678DOI Listing
April 2021

The triglycerides and glucose index is strongly associated with hepatic steatosis in children with overweight or obesity.

Eur J Pediatr 2021 Jun 25;180(6):1755-1760. Epub 2021 Jan 25.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, Mexico.

Given the worldwide increase prevalence of overweight, obesity, and nonalcoholic fatty liver disease (NAFLD), the objective of this study was to evaluate whether the triglycerides and glucose (TyG) index is associated with hepatic steatosis in children with overweight or obesity. Apparently healthy children aged 5‑17 years were included and allocated into the groups with and without hepatic steatosis. The TyG index was calculated as Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)]/2. Hepatic steatosis was diagnosed by ultrasonography. A total of 177 children, 66 (37.3%) girls and 111 (62.7%) boys, were included in the study. According to the hepatic ultrasonography, they were allocated into the groups with (n = 100) and without (n = 77) hepatic steatosis. The adjusted analysis by gender, body mass index, and waist circumference revealed that HDL-C (OR 0.96; 95% CI: 0.93-0.99), triglycerides (OR 1.005; 95% CI: 1.001-1.009), AST (OR 1.03; 95% CI: 1.008-1.07), ALT (OR 1.03; 95% CI: 1.01-1.05), and TyG index (OR 4.07; 95% CI: 1.26-13.15) remained associated with hepatic steatosis.Conclusion: Compared to other biochemical markers, the TyG index is highly associated with the presence of fatty liver in children with overweight and obesity. What is known: • The triglycerides and glucose (TyG) index is effective in predicting high risk for incident nonalcoholic fatty liver disease (NAFLD) in adults. What is new: • Compared to other biochemical markers, the TyG index is highly associated with the presence of fatty liver in children with overweight or obesity. • The triglycerides and glucose index may be a useful tool to detect children at high risk of fatty liver.
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http://dx.doi.org/10.1007/s00431-021-03951-1DOI Listing
June 2021

Familial hypercholesterolemia in Mexico: Initial insights from the national registry.

J Clin Lipidol 2021 Jan-Feb;15(1):124-133. Epub 2020 Dec 16.

Secretaria de la Defensa Nacional (SEDENA), Mexico City, Mexico.

Background: Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated.

Objective: Report the results of the first years (2017-2019) of the Mexican FH registry.

Methods: There are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations.

Results: To date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C <100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033).

Conclusion: The results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.
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http://dx.doi.org/10.1016/j.jacl.2020.12.001DOI Listing
December 2020

Effect of sodium-glucose co-transporter 2 inhibitors on hepatic parameters: A systematic review and meta-analysis of randomized controlled trials.

Pharmacol Res 2021 01 24;163:105319. Epub 2020 Nov 24.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, México. Electronic address:

Previous studies have suggested that sodium-glucose co-transporter-2 (SGLT2) inhibitors may improve hepatic function; however, the evidence is scarce. Hence, we performed a meta-analysis of randomized controlled trials to evaluate the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on hepatic parameters. PubMed, Web of Science, Scopus, and Google Scholar databases were searched to identify randomized controlled trials examining the effect of SGLT2 inhibitors on hepatic parameters. Meta-analysis was performed using a random-effects model and sensitivity analysis. Meta-analysis revealed that SGLT2 inhibitors therapy significantly lowered alanine aminotransferase (ALT) (WMD: -4.79 U/L, 95 % CI: -6.10, -3.47, I = 62 %, p < 0.00001), aspartate aminotransferase (AST) (WMD: -2.49 U/L, 95 % CI: -3.30, -1.68, I = 54 %, p < 0.00001), alkaline phosphatase (AP) (WMD: -1.13 U/L, 95 % CI: -2.03, -0.22, I = 23 %, p = 0.02), and gamma-glutamyl transferase (GGT) (WMD: -7.77 U/L, 95 % CI: -9.33, -6.21, I = 5 %, p < 0.00001). Additionally, SGLT2 inhibitors showed a significant increase in bilirubin levels (WMD: 0.64 U/L, 95 % CI: 0.27, 1.00, I = 53 %, p < 0.0006. Finally, no significant changes were found on albumin levels (WMD: 0.13 U/L, 95 % CI: -0.06, 0.32, I = 53 %, p < 0.0006) after SGLT2 inhibitors treatment. In conclusion, our results suggest that treatment with SGLT2 inhibitors exerts a beneficial effect on liver function tests through decreased ALT, AST, AP, and GGT concentrations.
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http://dx.doi.org/10.1016/j.phrs.2020.105319DOI Listing
January 2021

The Fat-to-Lean Mass Ratio Is Associated with Hyperinsulinemia in Healthy Mexican Adolescents.

J Am Coll Nutr 2021 Mar-Apr;40(3):219-223. Epub 2020 Oct 12.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, México.

To evaluate whether the Fat-to-Lean Mass (FyM) ratio is associated to hyperinsulinemia in healthy adolescents. Apparently healthy adolescents aged 10 to 15 years that according to sex, age, and percentiles of body fat percent, were included and allocated into the groups with elevated (body fat percent ≥85 percentile) and normal total body fat (body fat percent <85 percentile). The FyM ratio was calculated as total lean mass (kg)/total body fat (kg) and hyperinsulinemia was defined by fasting insulin levels ≥20 µUI/mL. A total of 1,299 adolescents, 665 (51.9%) girls and 634 (48.1%) boys, were enrolled and allocated into the groups with high (n = 439) and normal (n = 860) body fat. The FyM index remained significantly associated with hyperinsulinemia (OR 5.58; CI: 1.54-28.10) after logistic regression analysis adjusted by sex, age, body-weight, body mass index, and waist circumference. The FyM index is highly associated to the presence of hyperinsulinemia in adolescents, emerging as a useful tool from anthropometric measurements for identify insulin abnormalities.
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http://dx.doi.org/10.1080/07315724.2020.1752845DOI Listing
October 2020

Hypoglycemic and antioxidant properties of konjac (Amorphophallus konjac) in vitro and in vivo.

J Food Biochem 2020 12 7;44(12):e13503. Epub 2020 Oct 7.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, Mexico.

The aim of this study was to evaluate the hypoglycemic and antioxidant potential of konjac in vitro and in vivo. Glucose diffusion and enzymatic starch digestion of konjac were assayed using α-amylase and α-glucosidase. Oral glucose tolerance test (OGTT) and oral starch tolerance test (OSTT) were performed at dose of 102 mg/Kg of body weight (equivalent to 1 g/meal in humans). Additionally, the antioxidant activity of konjac was evaluated through inhibition of lipid peroxidation. The konjac decreased glucose diffusion by 36% and 19% compared with the negative and positive controls, respectively. Additionally, konjac inhibited α-amylase and α-glucosidase activities by 14% and 90%, respectively. After OSTT, group treated with konjac showed significant lower glucose levels compared with control group (p = .03). Finally, konjac reduced lipid peroxidation in human plasma (93%) compared with the negative control. Our results suggest that konjac exhibits hypoglycemic and antioxidant activities in vitro and in vivo. PRACTICAL APPLICATIONS: Because the use of herbal products have emerged as an attractive therapeutic option for chronic diseases, konjac administration may be an adjuvant for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1111/jfbc.13503DOI Listing
December 2020

Hypoglycemic and antioxidant effects of five commercial turmeric (Curcuma longa) supplements.

J Food Biochem 2020 09 21;44(9):e13389. Epub 2020 Jul 21.

Biomedical Research Unit of the Mexican Social Security Institute at Durango.

We evaluate the hypoglycemic and antioxidant effects of five commercial turmeric (Curcuma longa) supplements: (1) bulk samples, (2) turmeric root from India, (3) curcuma turmeric Pronat , (4) turmeric & black pepper Swanson , and (5) C3 complex turmeric curcumin. Glucose diffusion and enzymatic starch digestion assays, using α-amylase and α-glucosidase, were performed. The antioxidant activity of turmeric supplements was measured through lipid peroxidation inhibition and the scavenging radical assay. A starch dose of 102 mg/Kg of body weight (equivalent to 1 g/day in humans) was used to perform the oral starch tolerance test (OSTT) in Wistar male rats. All turmeric supplements decreased glucose diffusion and α-glucosidase enzyme activity, and inhibited lipid peroxidation. The rats that received bulk samples and CT showed significantly lower glucose levels than rats receiving acarbose and those of negative control group. Our results show that biological activities of turmeric supplements vary according to the commercial presentation. PRACTICAL APPLICATIONS: The study results suggest that the hypoglycemic and antioxidant effects of five commercial turmeric supplements vary among them. The information provided would be useful to physicians and individuals using these supplements.
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http://dx.doi.org/10.1111/jfbc.13389DOI Listing
September 2020

Effect of sodium-glucose co-transporter 2 inhibitors on lipid profile: A systematic review and meta-analysis of 48 randomized controlled trials.

Pharmacol Res 2020 10 8;160:105068. Epub 2020 Jul 8.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, México. Electronic address:

Previous studies have suggested additional beneficial effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors including the lipid-lowering effect; however, results on lipid profile are controversial. Thus, this meta-analysis aimed to determine the effect of SGLT2 inhibitors treatment on lipid levels in patients with type 2 diabetes. Randomized controlled trials assessing the impact of SGLT2 inhibitors on lipid parameters were searched in PubMed-MEDLINE, SCOPUS, Web of Science, and Google Scholar databases. Meta-analysis was conducted using a random-effects model and generic inverse variance method. Meta-analysis of 48 randomized controlled trials revealed that SGLT2 inhibitors therapy had a significant increase on total cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.05, 0.13, I = 79 %, p < 0.0001), LDL-cholesterol (WMD: 0.10 mmol/L, 95 % CI: 0.07, 0.12, I = 94 %, p < 0.00001), HDL-cholesterol (WMD: 0.06 mmol/L, 95 % CI: 0.05, 0.08, I = 99 %, p < 0.00001), and non-HDL-cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.06, 0.12, I = 96 %, p < 0.00001). Additionally, SGLT2 inhibitors administration showed a significant decrease in triglyceride levels (WMD: -0.10 mmol/L, 95 % CI: -0.13, -0.07, I = 96 %, p < 0.00001). Finally, no significant alteration was found on LDL/HDL ratio after SGLT2 inhibitors treatment (WMD: -0.01 mmol/L, 95 % CI: -0.05, 0.03, I = 99 %, p = 0.65). In conclusion, SGLT2 inhibitors significantly increase total cholesterol, LDL-cholesterol, non-HDL-cholesterol, and HDL-cholesterol, and decrease triglyceride levels.
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http://dx.doi.org/10.1016/j.phrs.2020.105068DOI Listing
October 2020

The Effect of Statins through Mast Cells in the Pathophysiology of Atherosclerosis: a Review.

Curr Atheroscler Rep 2020 05 26;22(5):19. Epub 2020 May 26.

Halal Research Center of IRI, FDA, Tehran, Iran.

Purpose Of Review: In this review, we discuss the evidence supporting the effects of statins on mast cells (MCs) in atherosclerosis and their molecular mechanism of action.

Recent Findings: Statins or HMG-CoA reductase inhibitors are known for their lipid-lowering properties and are widely used in the prevention and treatment of cardiovascular diseases. There is growing evidence that statins have an inhibitory effect on MCs, which contributes to the pleiotropic effect of statins in various diseases. MCs are one of the crucial effectors of the immune system which play an essential role in the pathogenesis of multiple disorders. Recent studies have shown that MCs are involved in the development of atherosclerotic plaques. MCs secrete various inflammatory cytokines (IL-6, IL4, TNF-α, and IFNγ) and inflammatory mediators (histamine, tryptase, proteoglycans) after activation by various stimulants. This, in turn, will exacerbate atherosclerosis. Statins suppress the activation of MCs via IgE inhibition which leads to inhibition of inflammatory mediators and cytokines which are involved in the development and progression of atherosclerosis. In keeping with this evidence presented here, MCs can be considered as one of the therapeutic targets for statins in the treatment of atherosclerosis.
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http://dx.doi.org/10.1007/s11883-020-00837-9DOI Listing
May 2020

Effect of Proton-Pump Inhibitors on Glucose and Insulin Metabolism on Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Curr Pharm Des 2020 ;26(32):4007-4013

Unidad de Investigacion Biomedica, Delegacion Durango, Instituto Mexicano del Seguro Social, Durango, Mexico.

Background: Some studies have revealed an improvement in glucose metabolism after proton-pump inhibitors (PPI) therapy; however, this evidence is inconclusive and limited.

Objective: The study aimed to examine the effect of PPI on glucose and insulin metabolism in patients with type 2 diabetes through a systematic review and meta-analysis.

Methods: Only randomized controlled trials evaluating the impact of PPI on glucose or insulin concentrations in type 2 diabetes were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases. A meta-analysis was conducted using a random-effects model and generic inverse variance method. Sensitivity analysis was performed using the leave-one-out method.

Results: Meta-analysis revealed no significant effect of PPI intervention on fasting glucose (mean difference [MD] -11.42 [95% CI, -29.68 to 6.83], I2 = 80%, p = 0.22), fasting insulin (MD 1.51 [95% CI, -0.36 to 3.37], I2 = 32%, p = 0.11), HOMA-IR (MD -0.16 [-0.98 to 0.65], I2 = 0%, p = 0.70), HOMA-β (MD 19.97 [-21.59 to 61.52], I2 = 71%, p = 0.35), and HbA1c concentrations (MD -0.34 [-0.99 to 0.31], I2 = 89%, p = 0.30).

Conclusion: The treatment with PPI, in the short term, had no significant effects on glucose and insulin metabolism in patients with type 2 diabetes.
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http://dx.doi.org/10.2174/1381612826666200523170718DOI Listing
January 2021

The correct formula for the triglycerides and glucose index.

Eur J Pediatr 2020 07 15;179(7):1171. Epub 2020 May 15.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Canoas 100, Col. Los Angeles, 34067, Durango, Dgo., Mexico.

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http://dx.doi.org/10.1007/s00431-020-03644-1DOI Listing
July 2020

Effect of ursodeoxycholic acid on liver markers: A systematic review and meta-analysis of randomized placebo-controlled clinical trials.

Br J Clin Pharmacol 2020 08 27;86(8):1476-1488. Epub 2020 Apr 27.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico.

Aim: The objective of this meta-analysis was to evaluate the effect of ursodeoxycholic acid (UDCA) therapy on serum liver function tests.

Methods: PubMed, Web of Science, Scopus and Google Scholar databases were searched to identify randomized placebo-controlled trials assessing the impact of UDCA on hepatic parameters. Meta-analysis was conducted using a random-effects model and sensitivity analysis through the leave-one-out method in the Review Manager statistical software version 5.3.

Results: After UDCA treatment, meta-analysis revealed a significant reduction of alanine aminotransferase (weighted mean difference [WMD]: -15.28 U/L, 95% confidence interval [CI]: -23.42, -7.15, P = 0.0002, I = 97%), aspartate aminotransferase (WMD: -16.13 U/L, 95% CI: -23.84, -8.42, P < 0.0001, I = 97%), gamma-glutamyl transferase (WMD: -23.29 U/L, 95% CI: -33.97, -12.61, P < 0.0001, I = 97%), alkaline phosphatase (WMD: -93.80 U/L, 95% CI: -126.36, -61.25, P < 0.0001, I = 95%) and bilirubin (WMD: -0.18 U/L, 95% CI: -0.35, -0.01, P = 0.04, I = 93%), but not significant changes in albumin levels (WMD: 0.10 U/L, 95% CI: -0.05, 0.24, P = 0.18, I = 80%).

Conclusion: The results of the present meta-analysis suggest a hepatoprotective effect of UDCA by reducing serum liver parameters.
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http://dx.doi.org/10.1111/bcp.14311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373700PMC
August 2020

The total body fat measured by bioelectrical impedance is associated with hyperinsulinaemia in apparently healthy adolescents.

Acta Paediatr 2020 09 10;109(9):1893-1894. Epub 2020 Mar 10.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, México.

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http://dx.doi.org/10.1111/apa.15224DOI Listing
September 2020

The triglyceride and glucose index is a useful biomarker to recognize glucose disorders in apparently healthy children and adolescents.

Eur J Pediatr 2020 Jun 3;179(6):953-958. Epub 2020 Feb 3.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Canoas 100, Col. Los Angeles, 34067, Durango, DGO, Mexico.

It has been suggested that the triglyceride and glucose (TyG) index is an early indicator for type 2 diabetes (T2D) in adults. Thus, the aim of this study was to evaluate whether the TyG index is useful in the screening of glucose disorders (GD) in apparently healthy children and adolescents. Eligible participants were apparently healthy children and adolescents. Individuals with new diagnosis of GD were allocated into the study groups with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and T2D. Participants with normal glucose tolerance (NGT) were the control group. In total, 1872 children and adolescents were enrolled and allocated into the study groups. Diagnosis of NGT, IFG, IGT, and T2D was established in 1541 (82.3%), 256 (13.7%), 66 (3.5%), and 9 (0.4%) children, respectively. In girls, the best cutoff points of the TyG index for identifying IFG, IGT, and T2D were 4.51 (sensitivity 59.8%, specificity 59.8%), 4.55 (sensitivity 63.0%, specificity 64.3%), and 4.63 (sensitivity 75.0%, specificity 74.6%), respectively; and in boys were 4.52 (sensitivity 62.8%, specificity 64.2%), 4.54 (sensitivity 71.8%, specificity 65.1%), and 4.82 (sensitivity 91.0%, specificity 990.6%), respectively.Conclusion: Our results suggest that the TyG index may be a useful tool for screening GD in healthy children and adolescents.What is Known:• Prevalence of prediabetes and type 2 diabetes is increasing worldwide among young adults and adolescents.• Elevated fasting glucose and triglyceride concentrations have been recognized as independent risk factors for type 2 diabetes.What is New:• The TyG index exhibited highest sensitivity and specificity to detect impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes.• The TyG index may be a useful tool for the screening of glucose disorders in apparently healthy children and adolescents.
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http://dx.doi.org/10.1007/s00431-020-03570-2DOI Listing
June 2020

Pulse wave velocity as a measure of arterial stiffness in patients with familial hypercholesterolemia: a systematic review and meta-analysis.

Arch Med Sci 2019 Oct 3;15(6):1365-1374. Epub 2019 Nov 3.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: The aim of this meta-analysis was to establish whether vascular pulse wave velocity (PWV) as a measure of arterial stiffness is changed in patients with familial hypercholesterolemia (FH).

Material And Methods: Studies comparing PWV between patients with FH and controls were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (up to November 26, 2017). A meta-analysis was conducted using Comprehensive Meta-Analysis V2 software. A random-effects model (using the DerSimonian-Laird method) and the generic inverse variance method were used to compensate for the heterogeneity of studies concerning demographic characteristics and differences in the studies' design.

Results: This meta-analysis of 8 studies involving 317 patients with FH and 244 non-FH individuals did not suggest a significantly altered PWV in FH patients versus controls (weighted mean difference (WMD): 0.17 m/s, 95% confidence interval (CI): -0.31, 0.65, = 0.489; = 80.15%). The result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. Subanalysis of 6 of these studies which had data on intima-media thickness (IMT) indicated an increased IMT in FH patients when compared with controls (WMD = 0.03 mm, 95% CI: 0.003, 0.06, = 0.034; = 48.95%). However, the effect size was sensitive to some of the included studies.

Conclusions: This meta-analysis suggests that FH patients do not have significantly altered PWV when compared with normocholesterolemic individuals. However, a subanalysis of studies in which IMT was measured indicated that IMT is increased in FH patients compared with controls.
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http://dx.doi.org/10.5114/aoms.2019.89450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855171PMC
October 2019

Effect of agave fructans on the production of short chain fatty acid in mice.

Food Sci Biotechnol 2019 Oct 23;28(5):1493-1498. Epub 2019 Feb 23.

2Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, Mexico.

The aim of this study was to evaluate the effect of agave fructans on short chain fatty acid (SCFA) production in mice (C57BL/6). Animals were randomly divided into three groups (n = 8): control group (CG), fructans from group (FG) (55 g per day/kg of body weight), and oligrofructose group (OG) (55 g per day/kg of body weight). Treatments were administered oral via for 6 weeks. After 24 days of treatment (phase 1), both treated groups exhibited elevated levels of acetic (12%) and propionic (FG 66% and OG 38%) acids in comparison with the CG. After 42 days of treatment (phase 2), FG had higher concentrations of acetic (33%) and propionic (73%) acids than the CG; while OG exhibited higher levels of butyric (12%) and propionic (35%) acids compared with the CG. Fructans from improve the production of SCFA in mice, suggesting a prebiotic activity.
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http://dx.doi.org/10.1007/s10068-019-00572-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811476PMC
October 2019

Efficacy and safety of avocado-soybean unsaponifiables for the treatment of hip and knee osteoarthritis: A systematic review and meta-analysis of randomized placebo-controlled trials.

Int J Rheum Dis 2019 Sep 22;22(9):1607-1615. Epub 2019 Jul 22.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, México.

Objective: We performed a systematic review and meta-analysis from randomized controlled trials to examine the efficacy and safety of avocado-soybean unsaponifiables (ASU) in patients with hip or knee osteoarthritis (OA).

Data Sources: Medline, SCOPUS, Web of Science, and Google Scholar databases were searched for randomized placebo-controlled trials.

Study Selection: Original studies were randomized placebo-controlled trials evaluating the effect of orally administered ASU on knee or hip OA symptoms using the Lequesne index, visual analog scale (VAS) and/or joint space width (JSW).

Data Extraction: Meta-analysis was conducted using a random-effects model and generic inverse variance method. Heterogeneity was tested using the I statistic index.

Data Synthesis: Avocado-soybean unsaponifiables therapy had a significant reduction on pain by VAS assessment (weighted mean difference [WMD]: -9.64 mm, 95% CI: -17.43, -1.84; P = .02; I  = 92%). A subanalysis according to the type of OA showed that ASU significantly decreased both VAS and Lequesne index in knee OA (WMD: -17.36, 95% CI: -25.91, -8.82; P < .0001; I  = 87% and WMD: -2.33, 95% CI: -2.88, -1.78; P < .00001; I  = 18%, respectively) but not in hip OA. Finally, ASU supplementation showed no significant differences for adverse events compared to placebo (relative risk: 1.02, 95% CI: 0.83, 1.25; P = .88; I  = 0%).

Conclusion: Results of this meta-analysis suggest a beneficial effect of ASU treatment in symptomatic knee OA but not in hip OA. Additionally, adverse events were similar in patients receiving ASU therapy or placebo.
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http://dx.doi.org/10.1111/1756-185X.13658DOI Listing
September 2019

Zinc deficiency is an independent risk factor for prehypertension in healthy subjects.

Int J Vitam Nutr Res 2021 Jan 1;91(1-2):25-30. Epub 2019 Jul 1.

Departamento de Bioquímica, Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Durango, México.

To assess whether zinc deficiency is associated with prehypertension (preHTN) in apparently healthy subjects. Apparently healthy women and men, aged 20 to 60 years were enrolled into a case-control study. Individuals with and without preHTN were allocated into the case and control groups, respectively. Hypertension, liver disease, renal disease, smoking, pregnancy, diabetes, malignancy, hypernatremia, hypomagnesemia, medical treatment, and use of supplements containing zinc were exclusion criteria. PreHTN was defined by systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) of 120-139 mmHg and/or of 80-89 mmHg, respectively, and the zinc deficiency by serum zinc levels < 74 μg/dL in men and < 70 μg/dL in women. In total, 142 subjects (90 women and 52 men) were enrolled and allocated in the case (n = 71) and control (n = 71) groups. In the overall population, the frequency of zinc deficiency was 11.1%; individuals in the case group showed significant higher frequency of zinc deficiency as compared with the control group (16.9% vs 5.5%, p = 0.04). The logistic regression analysis showed a significant association between zinc deficiency and preHTN (OR = 4.61; 95% CI: 1.24-17.12, p = 0.02). Our results suggest that zinc deficiency is associated with the presence of preHTN in apparently healthy subjects.
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http://dx.doi.org/10.1024/0300-9831/a000593DOI Listing
January 2021

The triglycerides and glucose index is associated with elevated blood pressure in apparently healthy children and adolescents.

Eur J Pediatr 2019 Jul 12;178(7):1069-1074. Epub 2019 May 12.

Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Canoas 100, Col. Los Angeles, 34067, Durango, Mexico.

Prevalence of elevated blood pressure in pediatric population has been increasing worldwide. Thus, the aim of this study was to examine whether the triglycerides and glucose (TyG) index is associated with the presence of prehypertension or hypertension in children and adolescents. Apparently healthy children aged 6 to 15 years were enrolled in a population-based cross-sectional study. Participants were allocated into groups with normal blood pressure (NBP), prehypertension, and hypertension. Smoking, alcohol intake, pregnancy, previous diagnosis of diabetes, kidney, hepatic, or endocrine diseases were exclusion criteria. NBP was defined by systolic and/or diastolic blood pressure < 90th percentile, prehypertension by systolic and/or diastolic blood pressure ≥ 90th < 95th percentile, and hypertension by systolic and/or diastolic blood pressure ≥ 95th percentile, according to age, sex, and height percentiles. A total of 3589 children were enrolled, 1748 (49%) girls and 1841 (51%) boys, and allocated into groups with NBP (n = 2874), prehypertension (n = 271), and hypertension (n = 444). The multiple logistic regression analysis stratified by age and adjusted by the Z-score/SDS of body mass index and waist circumference showed that elevated TyG index was significantly associated with prehypertension (OR = 1.48; 95% CI: 1.08-2.05) and hypertension (OR = 1.63; 95% CI: 1.26-2.11).Conclusion: The results of the present study shows that the elevated TyG index is significantly associated with the presence of prehypertension and hypertension in children and adolescents. What is Known: • Prevalence of elevated blood pressure in children and adolescents has been increasing worldwide. • Insulin resistance plays a key role in the pathogenesis of hypertension. What is New: • The elevated TyG index is significantly associated with the presence of prehypertension in children aged 6-9 years and adolescents aged 10-15 years. • The elevated TyG index is significantly associated with the presence of hypertension in children aged 6-9 years and adolescents aged 10-15 years.
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http://dx.doi.org/10.1007/s00431-019-03392-xDOI Listing
July 2019
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