Update on Neonatal Isolated Hyperthyrotropinemia: A Systematic Review.

The purpose of this paper was to systematically summarize the published literature on neonatal isolated hyperthyrotropinemia (HTT), with a focus on prevalence, L-T4 management, re-evaluation of thyroid function during infancy or childhood, etiology including genetic variation, thyroid imaging tests, and developmental outcome. Electronic and manual searches were conducted for relevant publications, and a total of 46 articles were included in this systematic review. The overall prevalence of neonatal HTT was estimated at 0.06%. The occurrence of abnormal imaging tests was found to be higher in the persistent than in the transient condition. A continuous spectrum of thyroid impairment severity can occur because of genetic factors, environmental factors, or a combination of the two. Excessive or insufficient iodine levels were found in 46% and 16% of infants, respectively. Thirty-five different genetic variants have been found in three genes in 37 patients with neonatal HTT of different ethnic backgrounds extracted from studies with variable design. In general, genetic variants reported in the TSHR gene, the most auspicious candidate gene for HTT, may explain the phenotype of the patients. Many practitioners elect to treat infants with HTT to prevent any possible adverse developmental effects. Most patients with thyroid abnormalities and/or carrying monoallelic or biallelic genetic variants have received L-T4 treatment. For all those neonates on treatment with L-T4, it is essential to ensure follow-up until 2 or 3 years of age and to conduct medically supervised trial-off therapy when warranted. TSH levels were found to be elevated following cessation of therapy in 44% of children. Withdrawal of treatment was judged as unsuccessful, and medication was restarted, in 78% of cases. Finally, data extracted from nine studies showed that none of the 94 included patients proved to have a poor developmental outcome (0/94). Among subjects presenting with normal cognitive performance, 82% of cases have received L-T4 therapy. Until now, the precise neurodevelopmental risks posed by mild disease remain uncertain.

Meta-analytic evidence for increased low-grade systemic inflammation and oxidative stress in hypothyroid patients. Can levothyroxine replacement therapy mitigate the burden?

PURPOSE: This series of meta-analyses were aimed to elucidate the impact of hypothyroidism on low-grade systemic inflammation and oxidative stress assessed by C-reactive protein (CRP) and malondialdehyde (MDA) respectively; and to evaluate the effect of levothyroxine replacement therapy (LRT) on those outcomes. METHODS: PubMed database and the key studies references were searched prior to March 3, 2020. Data on serum or plasma CRP and MDA levels in SHT (subclinical) and/or OHT (overt) hypothyroid patients and controls were extracted to compute overall standardized mean differences (SMD) by the random-effects model. RESULTS: A total of 93 studies were entered into analyses and ten main meta-analyses were performed. OHT (SMD = 0.72 [0.39; 1.04], k = 35), SHT (SMD = 1.58 [0.78; 2.38], k = 56) and even mild SHT (TSH < 10 mU/L, SMD = 2.19 [0.02; 4.37], k = 13) proved to have a detrimental effect on CRP levels. LRT showed a favorable effect on CRP levels, particularly in OHT (SMD = -0.30 [-0.57; -0.02], k = 17). Increased levels of MDA were also found, especially in OHT (SMD = 2.49 [0.66; 4.31], k = 13). LRT may also improve MDA levels; however future studies would further validate the advantageous effect of LRT in hypothyroidism. Heterogeneity primarily originated from different study designs and geographic locations. CONCLUSION: Overall, these meta-analyses reveal that screening for hs-CRP and MDA in hypothyroid patients as simple biomarkers of low-grade systemic inflammation and oxidative stress may become a useful tool to identify those at increased risk who may benefit most from early interventions.

Influence of prenatal stress on metabolic abnormalities induced by postnatal intake of a high-fat diet in BALB/c mice.

Prenatal insults during fetal development result in increased likelihood of developing chronic disease. Obesity, the biggest risk factor for the development of metabolic disease, is affected by several genetic and environmental factors. High-fat diet (HFD) consumption is usually linked with the development of obesity. The main goal of this study was to analyze the impact of the exposure to a HFD in prenatally stressed animals. For this purpose, we subjected pregnant BALB/c mice to restraint stress for 2 h a day between gestational day (GD) 14 and GD 21. Prenatally stressed and control offspring of both sexes were postnatally exposed to a HFD for 24 weeks. We found that prenatal stress (PS) per se produced disturbances in males such as increased total blood cholesterol and triglycerides, with a decrease in mRNA expression of sirtuin-1. When these animals were fed a HFD, we observed a rise in glucose and insulin levels and an increase in visceral adipose tissue gene expression of leptin, resistin, and interleukin-1 beta. Although females proved to be more resilient to PS consequences, when they were fed a HFD, they showed significant metabolic impairment. In addition to the changes observed in males, females also presented an increase in body weight and adiposity and a rise in cholesterol levels.

Perinatal taurine exerts a hypotensive effect in male spontaneously hypertensive rats and down-regulates endothelial oxide nitric synthase in the aortic arch.

Essential hypertension is considered to be a result of the interaction between genetic and environmental factors, including perinatal factors. Different advantageous perinatal factors proved to have beneficial long-lasting effects against an abnormal genetic background. Taurine is a ubiquitous sulphur-containing amino acid present in foods such as seafood. The antihypertensive effects of taurine have been reported in experimental studies and in human hypertension. We aimed to investigate the effects of perinatal treatment with taurine in spontaneously hypertensive rats (SHR), a known model of genetic hypertension. Female SHR were administered with taurine (3 g/L) during gestation and lactation (SHR-TAU). Untreated SHR and Wistar-Kyoto rats (WKY) were used as controls. Long-lasting effects in offspring were investigated. Addition of taurine to the mother's drinking water reduced blood pressure in adult offspring. No differences were observed in cardiac hypertrophy. Findings on morphometric evaluations suggest that perinatal treatment with taurine would be partially effective in improving structural alterations of the aorta. Modifications in gene expression of Bcl-2 family members and upregulation of endothelial nitric oxide synthase in the aorta of 22-week-old male offspring were found. No differences were observed on relative telomere length in different cardiovascular tissues between SHR and SHR-TAU. Altogether results suggest that taurine programming, albeit sex specific, is associated with gene expression changes which ultimately may lead to improvement of aortic remodelling and enhanced endothelial function because of augmented nitric oxide (NO) production.

Systematic review and meta-analysis on the relationship between prenatal stress and metabolic syndrome intermediate phenotypes.

BACKGROUND: Metabolic Syndrome (MetS) can be considered as a consequence of a complex interplay between genetic and environmental factors and can be influenced by changes in the environment early in life. Prenatal stress (PS) exposure likely represents an important adverse intrauterine environment that may impact the biology of the developing organism. The aim of this study was to quantitatively synthesize the available data on the effects of PS on offspring's obesity, estimated indirectly by body mass index (BMI) and body fat; blood pressure, plasma glucose and blood lipid concentrations (triglycerides and high-density lipoprotein cholesterol). METHODS: Literature searches for eligible studies on PubMed were conducted until October 8, 2018. Full text review yielded 24 publications for inclusion into the systematic review. Meta-analyses were performed for the outcomes BMI and body fat. 62 effect sizes from 19 studies together with relevant moderators were collected. Summary estimates were calculated by using random-effects model. RESULTS: The combined standardized mean difference (d) for the relation between BMI and PS indicated that despite significant heterogeneity, stress exposure of expectant mothers was associated with increased BMI of their offspring [d (95% CI) = 0.268 (0.191; 0.345)]. Both objective and subjective stress have been linked to increased overweight. Preliminary results of the relationship between PS and body fat suggested that the contribution of PS to body fat should be at least further considered [d (95% CI) = 0.167 (0.016; 0.317)]. Evidence from a limited number of published studies do not sustains an effect on blood pressure, glucose metabolism or circulating lipids, however these outcomes have only been scarcely investigated. CONCLUSIONS: A direct association between PS and BMI was found and further studies are needed to confirm the relationship between maternal stress during gestation and body fat. Overall, findings suggest that PS could contribute to alterations to the post-natal offspring phenotype.

Biochemical and MALDI-TOF Mass Spectrometric Characterization of a Novel Native and Recombinant Cystine Knot Miniprotein from Solanum tuberosum subsp. andigenum cv. Churqueña.

Cystine-knot miniproteins (CKMPs) are an intriguing group of cysteine-rich molecules that combine the characteristics of proteins and peptides. Typically, CKMPs are fewer than 50 residues in length and share a characteristic knotted scaffold characterized by the presence of three intramolecular disulfide bonds that form the singular knotted structure. The knot scaffold confers on these proteins remarkable chemical, thermal, and proteolytic stability. Recently, CKMPs have emerged as a novel class of natural molecules with interesting pharmacological properties. In the present work, a novel cystine-knot metallocarboxypeptidase inhibitor (chuPCI) was isolated from tubers of Solanum tuberosum, subsp. andigenum cv. Churqueña. Our results demonstrated that chuPCI is a member of the A/B-type family of metallocarboxypeptidases inhibitors. chuPCI was expressed and characterized by a combination of biochemical and mass spectrometric techniques. Direct comparison of the MALDI-TOF mass spectra for the native and recombinant molecules allowed us to confirm the presence of four different forms of chuPCI in the tubers. The majority of such forms have a molecular weight of 4309 Da and contain a cyclized Gln in the N-terminus. The other three forms are derived from N-terminal and/or C-terminal proteolytic cleavages. Taken together, our results contribute to increase the current repertoire of natural CKMPs.

The Association between High Fat Diet around Gestation and Metabolic Syndrome-related Phenotypes in Rats: A Systematic Review and Meta-Analysis.

Numerous rodent studies have evaluated the effects of a maternal high-fat diet (HFD) on later in life susceptibility to Metabolic Syndrome (MetS) with varying results. Our aim was to quantitatively synthesize the available data on effects of maternal HFD around gestation on offspring's body mass, body fat, plasma leptin, glucose, insulin, lipids and systolic blood pressure (SBP). Literature was screened and summary estimates of the effect of maternal HFD on outcomes were calculated by using fixed- or random-effects models. 362 effect sizes from 68 studies together with relevant moderators were collected. We found that maternal HFD is statistically associated with higher body fat, body weight, leptin, glucose, insulin and triglycerides levels, together with increased SBP in offspring later in life. Our analysis also revealed non-significant overall effect on offspring's HDL-cholesterol. A main source of variation among studies emerged from rat strain and lard-based diet type. Strain and sex -specific effects on particular data subsets were detected. Recommendations are suggested for future research in the field of developmental programming of the MetS. Despite significant heterogeneity, our meta-analysis confirms that maternal HFD had long-term metabolic effects in offspring.

Telomere length in the two extremes of abnormal fetal growth and the programming effect of maternal arterial hypertension.

We tested the hypothesis that leukocyte telomere length (LTL) is associated with birth weight in both extremes of abnormal fetal growth: small (SGA) and large for gestational age newborns (LGA). Clinical and laboratory variables of the mothers and the neonates were explored; 45 newborns with appropriate weight for gestational age (AGA), 12 SGA and 12 LGA were included. Whether the differences might be explained by variation in OBFC1 (rs9419958) and CTC1 (rs3027234) genes associated with LTL was determined. A significant association between birth weight and LTL was observed; LTL was significantly shorter in LGA newborns (1.01 ± 0.12) compared with SGA (1.73 ± 0.19) p < 0.005, mean ± SE. Maternal (Spearman R = -0.6, p = 0.03) and neonatal LTL (R = -0.25, p = 0.03) were significantly and inversely correlated with maternal history of arterial hypertension in previous gestations. Neonatal LTL was not significantly associated with either rs9419950 or rs3027234, suggesting that the association between neonatal LTL and birth weight is not influenced by genetic variation in genes that modify the interindividual LTL. In conclusion, telomere biology seems to be modulated by abnormal fetal growth; modifications in telomere length might be programmed by an adverse environment in utero.

Association between ß2-adrenoceptor (ADRB2) haplotypes and insulin resistance in PCOS.

OBJECTIVE: The aim of this study was to explore ß2-adrenoceptor (ADRB2) haplotype associations with phenotypes and quantitative traits related to insulin resistance (IR) and the metabolic syndrome (MS) in a polycystic ovary syndrome (PCOS) population. A secondary purpose was to assess the association between ADRB2 haplotype and PCOS. DESIGN: Genetic polymorphism analysis. Cross-sectional case-control association study. SETTING: Medical University Hospital and research laboratory. PATIENTS: One hundred and sixty-five unrelated women with PCOS and 116 unrelated women without PCOS (control sample). MEASUREMENTS: Clinical and biochemical measurements, and ADRB2 genotyping in PCOS patients and control subjects. METHODS: ADRB2 haplotypes (comprising rs1042711, rs1801704, rs1042713 and rs1042714 in that order), genotyping and statistical analysis to evaluate associations with continuous variables and traits related to IR and MS in a PCOS population. Associations between ADRB2 haplotypes and PCOS were also assessed. RESULTS: We observed an age-adjusted association between ADRB2 haplotype CCGG and lower insulin (P = 0·018) and HOMA (P = 0·008) in the PCOS sample. Interestingly, the expected differences in surrogate measures of IR between cases and controls were not significant in CCGG/CCGG carriers. In the case-control study, genotype CCGG/CCGG was associated with a 14% decrease in PCOS risk (P = 0·043), taking into account confounding variables. CONCLUSIONS: Haplotype I (CCGG) has a protective role for IR and MS in PCOS.

Functional characterization of TLR4 +3725 G/C polymorphism and association with protection against overweight.

Subclinical low-grade systemic inflammation has been associated with obesity, insulin resistance and metabolic syndrome (MS). Recent studies have highlighted the role of gut microbiota in these disorders. The toll-like receptor 4 (TLR4) plays a key role in the innate immune response activation. We studied two polymorphisms (+3725G/C and 11350G/C) in the 3' untranslated region (3'UTR) of the TLR4 gene that may alter its expression and their association with metabolic disorders related to systemic inflammation. We cloned the 3'UTR into a luciferase reporter system and compared wild-type 3'UTR (WT) and +3725C variant (MUT) constructs luciferase activities. MUT construct reduced the reporter gene activity by 30% compared to WT (P = 0.0001). To evaluate the association between these polymorphisms with biochemical and clinical overweight related variables, we conducted a population cross-sectional study in 966 men of Argentine general population. Considering smoking as a confounding variable that causes systemic inflammation, we studied these possible effects in both, smokers and nonsmokers. The 11350G/C polymorphism was not detected in our sample whereas the CC genotype of +3725 polymorphism was associated with lean subjects (p = 0.011) and higher Adiponectin levels (p = 0.021). Subjects without any NCEP/ATP III MS component were associated with this genotype as well (p = 0.001). These results were strengthened in nonsmokers, in which CC genotype was associated with lean subjects (p = 0.003) and compared with G carriers showed significantly lower BMI (25.53 vs. 28.60 kg/m2; p = 0.023) and waist circumference (89.27 vs. 97.51 cm; p = 0.025). None of these associations were found in smokers. These results showed that +3725C variant has a functional effect down-regulating gene expression and it could be considered as a predictive factor against overweight, particularly in nonsmokers. Considering the role of TLR4 in inflammation, these findings would suggest that the presence of +3725C variant could predict a lower prevalence of chronic metabolic disorders.

[Obesity and risk factors for metabolic syndrome in young people with type 1 diabetes]. / Obesidad y factores de riesgo del síndrome metabólico en jóvenes con diabetes tipo 1.

Changes in the clinical presentation of diabetes mellitus in childhood and adolescence associated with obesity have resulted in an overlap of the two most common types of diabetes with a greater clinical heterogeneity. In order to characterize the type of diabetes at onset and assess the effect of obesity, 50 children with diabetes were studied. The patients were divided into two groups according to their nutritional status at diagnosis (over-weight/obese vs. normal weight). Insulin reserve was evaluated by measuring basal C-peptide and stimulated C-peptide in response to a mixed meal (MMTT) as well as HLA-DQB1 genotype, antibodies, and family history of risk factors for metabolic disease. Of all 50 patients, 38% was overweight/obese, 84% had a positive family history of metabolic syndrome, 82% had positive antibodies, and 100% were positive for the high-risk HLA-DQB1 genotype. No significant differences were found in fasting C-peptide or glycemic index/C-peptide levels between the two groups. In the overweight/obese group C-peptide response to MMTT showed higher levels at 60 and 120 minutes (p = 0.02 and 0.03) and the area under the curve for C-peptide was also higher (1.77 ng / ml vs. 5.5 ng/ ml, p = 0.0007) than in the normal-weight group. In conclusion, overweight/obese patients with type 1A diabetes had a greater pancreatic reserve, suggesting that nutritional status may accelerate disease onset.

Association of common variants in JAK2 gene with reduced risk of metabolic syndrome and related disorders.

BACKGROUND: Disturbances in leptin and insulin signaling pathways are related to obesity and metabolic syndrome (MS) with increased risk of diabetes and cardiovascular disease. Janus kinase 2 (JAK2) is a tyrosine kinase involved in the activation of mechanisms that mediate leptin and insulin actions. We conducted a population cross-sectional study to explore the association between two common variants in JAK2 gene and MS related traits in 724 Argentinean healthy male subjects. METHODS: A total of 724 unrelated men aged 37.11 ± 10.91 yr were included in a cross-sectional study. Physical examination, anthropometric measurements and biochemical analysis were determined by a standardized protocol. rs7849191 and rs3780378 were genotyped. Analyses were done separately for each SNP and followed up by haplotype analysis. RESULTS: rs7849191 and rs3780378 were both associated with reduced risk of MS [p = 0.005; OR (95%CI) = 0.52 (0.33-0.80) and p = 0.006; OR (95% CI) = 0.59 (0.40-0.86) respectively, assuming a dominant model]. rs3780378 T allele was associated with triglyceridemia values under 150 mg/dl [p = 0.007; OR (95%CI) = 0.610 (0.429-0.868)] and TT carriers showed lower triglycerides (p = 0.017), triglycerides/HDL-C ratio (p = 0.022) and lipid accumulation product (p = 0.007) compared to allele C carriers. The two-SNPs-haplotype analysis was consistent with single locus analysis. CONCLUSIONS: It was found for the first time, significant associations of JAK2 common variants and related haplotypes with reduced risk of MS. These findings could be explained by the role of JAK2 in insulin and/or leptin signaling.

The rs1801278 G>A polymorphism of IRS-1 is associated with metabolic syndrome in healthy nondiabetic men. Modulation by cigarette smoking status.

AIMS: To explore associations between IRS-1 rs1801278 G>A polymorphism and metabolic syndrome (MS). METHODS: rs1801278 G>A was genotyped in 610 healthy Argentinian men. RESULTS: GA carriers had lower risk of MS (OR=0.52, P=0.045), particularly among smokers (OR=0.10, P=0.006). CONCLUSIONS: rs1801278 GA carriers had lower risk of MS, especially among smokers.

Association of the TGrI29 microsatellite in thyroglobulin gene with autoimmune thyroiditis in a Argentinian population: a case-control study.

Autoimmune thyroid disease (AITD) is a multifactorial disorder that involves a putative association with thyroid autoantigen-specific and immune regulatory genes, as well as environmental factors. The thyroglobulin gene is the main identified thyroid autoantigen-specific gene associated to autoimmune thyroiditis. The aim of this work was to test for evidence of allelic association between autoimmune thyroiditis (AT) and thyroglobulin polymorphism markers in Argentinian patients. We studied six polymorphisms distributed throughout all the thyroglobulin gene: four microsatellites (Tgms1, Tgms2, TGrI29, and TGrI30), one insertion/deletion polymorphism (IndelTG-IVS18), and one exonic single nucleotide polymorphism (c.7589G>A) in 100 AT patients and 100 healthy control subjects. No differences in allele and genotype frequencies distribution were observed between autoimmune thyroiditis cases and controls for Tgms1, Tgms2, TGrI30, IndelTG-IVS18, and c.7589G>A. However, when we analyzed autoimmune thyroiditis patients with the TGrI29 microsatellite we found a significant association between the 197-bp allele and autoimmune thyroiditis (33.50% vs. 19.00% in control group) (P = 0.001). In addition, a significant major prevalence of the 197/201-bp genotype has been also seen in autoimmune thyroiditis subjects (59% vs. 24% in control group, P < 0.0001). In conclusion, our work showed the association between the thyroglobulin gene and autoimmune thyroiditis in Argentinian population and supports the described evidence of thyroglobulin as a thyroid-specific gene linked to AITD.

A functional nonsynonymous toll-like receptor 4 gene polymorphism is associated with metabolic syndrome, surrogates of insulin resistance, and syndromes of lipid accumulation.

Toll-like receptor 4 (TLR4) plays a key role in the activation of innate immune responses. Loss-of-function mutations in TLR4 prevent diet-induced obesity and insulin resistance (IR). We conducted a population cross-sectional study to evaluate whether Asp299Gly (rs4986790) TLR4 gene polymorphism is associated with metabolic syndrome (MS), surrogates of IR, and syndromes of lipid accumulation (SLAs) in Argentinean healthy male subjects. rs4986790 was genotyped in 621 healthy unrelated male blood donors. National Cholesterol Education Program/Adult Treatment Panel III-MS (NCEP/ATP III-MS); SLAs such as enlarged waist elevated triglyceride syndrome (EWET), hypertriglyceridemic waist (HW), and overweight-lipid syndrome (OLS); and surrogates of IR were assessed. The prevalence of MS, OLS, and EWET was significantly higher among Asp299Asp carriers (P < .05). These findings were confirmed using 32 000 bootstrap samples. Surrogate markers of IR were also significantly higher in Asp299Asp carriers (P < .05). Most findings were especially strengthened among individuals with C-reactive protein below the 95th percentile and/or total cholesterol to high-density lipoprotein cholesterol ratio >or=5. This is the first report to find, in Argentinean healthy male blood donors, associations between the Asp299Asp genotype of rs4986790 TLR4 gene polymorphism and high risk for NCEP/ATP III-MS, SLAs, and surrogates of IR. These findings are consistent with previous functional and observational studies showing that Asp299 allele, in comparison with Gly299, is associated with increased TLR4 activation, higher levels of inflammatory cytokines, acute-phase reactants and soluble adhesion molecules, and higher risk of atherosclerosis.

Pro12Ala polymorphism of the peroxisome proliferatoractivated receptor-gamma gene is associated with metabolic syndrome and surrogate measures of insulin resistance in healthy men: interaction with smoking status.

BACKGROUND: The Pro12Ala polymorphism (rs1801282), a nonsynonymous substitution of peroxisome proliferator-activated receptor-gamma (PPARG), has been robustly associated with type 2 diabetes. However, its role in metabolic syndrome (MetS) remains poorly understood. The associations among rs1801282, MetS and surrogate measures of insulin resistance (IR) were investigated in the present study. METHODS AND RESULTS: A cross-sectional population-based survey of 572 unrelated healthy male Argentinian blood donors with normal findings on medical examination and not taking any medication was conducted. MetS was assessed using the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) criteria, and the HOMA-IR, and QUICKI were calculated. Genotyping of rs1801282 was performed using RFLP-PCR. The prevalence of MetS was 26.2%. The Pro/Ala genotype (and the Ala12 allele) was associated with a high risk for MetS (odds ratio (OR) 1.67 [95% confidence interval (CI) 1.03-2.72], P=0.0394). This was highlighted among nonsmokers (OR 2.20 [95%CI 1.25-3.88], P=0.0059). ANCOVA confirmed an interaction between smoking status and this association (P=0.031). Ala12 carriers had a higher waist circumference than noncarriers (P=0.0065). Among nonsmokers, surrogates of IR, such as HOMA-IR, were significantly higher in Ala12 carriers than in noncarriers (P<0.05). CONCLUSIONS: Healthy men, in particular nonsmokers, carrying the Ala12 allele of PPARG rs1801282 polymorphism, have a high risk for MetS and IR.