Enrique Teran

GH Receptor Deficiency in Ecuadorian Adults Is Associated With Obesity and Enhanced Insulin Sensitivity

CONTEXTnEcuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity.nnnOBJECTIVEnWe sought to determine the metabolic associations for this phenomenon.nnnDESIGNnFour studies were carried out: 1) glucose, lipid, adipocytokine concentrations; 2) metabolomics evaluation; 3) metabolic responses to a high-calorie meal; and 4) oral glucose tolerance tests.nnnSETTINGnClinical Research Institute in Quito, Ecuador.nnnSUBJECTSnAdults homozygous for the E180 splice mutation of the GH receptor (GHRD) were matched for age, gender, and body mass index with unaffected control relatives (C) as follows: study 1, 27 GHRD and 35 C; study 2, 10 GHRD and 10 C; study 3, seven GHRD and 11 C; and study 4, seven GHRD and seven C.nnnRESULTSnAlthough GHRD subjects had greater mean percentage body fat than controls, their fasting insulin, 2-hour blood glucose, and triglyceride levels were lower. The indicator of insulin sensitivity, homeostasis model of assessment 2%S, was greater (P < .0001), and the indicator of insulin resistance, homeostasis model of assessment 2-IR, was lower (P = .0025). Metabolomic differences between GHRD and control subjects were consistent with their differing insulin sensitivity, including postprandial decreases of branched-chain amino acids that were more pronounced in controls. High molecular weight and total adiponectin concentrations were greater in GHRD (P = .0004 and P = .0128, respectively), and leptin levels were lower (P = .02). Although approximately 65% the weight of controls, GHRD subjects consumed an identical high-calorie meal; nonetheless, their mean glucose concentrations were lower, with mean insulin levels one-third those of controls. Results of the 2-hour oral glucose tolerance test were similar.nnnMAIN OUTCOME MEASURESnMeasures of insulin sensitivity, adipocytokines, and energy metabolites.nnnCONCLUSIONSnWithout GH counter-regulation, GHRD is associated with insulin efficiency and obesity. Lower leptin levels, despite higher percentage body fat, suggest that obesity-associated leptin resistance is GH dependent. Elevated adiponectin levels not correlated with percentage body fat indicate that GH signaling is necessary for their typical suppression with obesity.

CYP2D6 genotype and dextromethorphan hydroxylation phenotype in an Ecuadorian population

PurposeCytochrome P450 2D6 (CYP2D6) genotypes and the dextromethorphan/dextrorphan (DXM/DXT) metabolic ratio (MR), which is a marker of CYP2D6 activity, were studied in 118 unrelated healthy Ecuadorians.MethodsGenotyping of CYP2D6 was performed by amplification of entire CYP2D6 gene by XL-PCR for CYP2D6*5 and multiplication alleles and by real time-PCR for CYP2D6*2, *3, *4, *6, *10, *17, *29, *35, *41, and copy number. The plasma levels of DXM and its metabolite DXT were determined on a high-performance liquid chromatography–UV system.ResultsThe proportions of non-functional alleles were 0.4, 10.6, 0.8, 2.1, and 0% for CYP2D6*3, *4, *4u2009×u2009N, *5, and *6, respectively. Genotypically, only one of the subjects (0.9%) was homozygous for two inactive alleles and phenotypically classified as a poor metabolizer (PM). The MRs (mean ± standard deviation) corresponding to “activity scores” of 0, 0.5, 1, 1.5, 2, and 2.5 were 10.57 (nu2009=u20091), 1.63u2009±u20090.35 (nu2009=u20092), 1.16u2009±u20090.74 (nu2009=u200929), 1.00u2009±u20090.47 (nu2009=u20098), 1.24u2009±u20090.82 (nu2009=u200976), and 1.30u2009±u20090.32 (nu2009=u20092), respectively.ConclusionsOur data suggest that only 1% of subjects of this Ecuadorian population were PMs and that none were phenotypically ultrarapid metabolizers, which is in agreement with previous findings in other Amerindian populations.

Losartan hydroxylation phenotype in an Ecuadorian population: influence of CYP2C9 genetic polymorphism, habits and gender

AIMnTo describe for the first time CYP2C9 hydroxylation phenotype with CYP2C9 genotypes in a Hispanic (Ecuadorian) population using losartan; and the relevance of gender, tobacco, ethanol and caffeine consumption on the enzyme hydroxylation capacity.nnnMETHODSnEcuadorian healthy volunteers (n = 194) received a single oral dose of 25 mg losartan. Losartan metabolic ratio was defined as losartan:E3174 concentration. CYP2C9 alleles *2, *3, *4, *5 and *6 were analyzed.nnnRESULTSnNo phenotypically poor metabolizers were found. The metabolic ratio (mean ± standard deviation) was higher (p < 0.05) in CYP2C9*1/*3 carriers (12.4 ± 13.8; n = 6) versus CYP2C9*1/*1 (4.9 ± 7.0; n = 167), as well as in females versus males (6.72 ± 9.72 and 3.76 ± 4.48, respectively; p < 0.05). Only the following genotypes, CYP2C9*1/*1, CYP2C9*1/*2 and CYP2C9*1/*3, were found with a frequency of 86.1%, 10.8% and 3.1%, respectively.nnnCONCLUSIONnDespite the mean metabolic ratio being higher in this population than in others previously studied across genotypes, no poor metabolizers, either phenotypically or genotypically, were found.

Perception of the Usefulness of Drug/Gene Pairs and Barriers for Pharmacogenomics in Latin America

Pharmacogenetics and Pharmacogenomics areas are currently emerging fields focused to manage pharmacotherapy that may prevent undertreatment while avoiding associated drug toxicity in patients. Large international differences in the awareness and in the use of pharmacogenomic testing are presumed, but not well assessed to date. In the present study we review the awareness of Latin American scientific community about pharmacogenomic testing and the perceived barriers for their clinical application. In order to that, we have compiled information from 9 countries of the region using a structured survey which is compared with surveys previously performed in USA and Spain. The most relevant group of barriers was related to the need for clear guidelines for the use of pharmacogenomics in clinical practice, followed by insufficient awareness about pharmacogenomics among clinicians and the absence of regulatory institutions that facilitate the use of pharmacogenetic tests. The higher ranked pairs were TPMT/thioguanine, TPMT/azathioprine, CYP2C9/warfarin, UGT1A1/irinotecan, CYP2D6/amitriptiline, CYP2C19/citalopram and CYP2D6/clozapine. The lower ranked pairs were SLCO1B1/simvastatin, CYP2D6/metoprolol and GP6D/chloroquine. Compared with USA and Spanish surveys, 25 pairs were of lower importance for Latin American respondents. Only CYP2C19/esomeprazole, CYP2C19/omeprazole, CYP2C19/celecoxib and G6PD/dapsone were ranked higher or similarly to the USA and Spanish surveys. Integration of pharmacogenomics in clinical practice needs training of healthcare professionals and citizens, but in addition legal and regulatory guidelines and safeguards will be needed. We propose that the approach offered by pharmacogenomics should be incorporated into the decision-making plans in Latin America.

Relationship between the CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthy Ecuadorian volunteers.

AIMnThe CYP2C9 IVS8-109T allele was recently found to be more frequent among Swedish individuals, who have the highest losartan metabolic ratio (MR; losartan:E-3174). Thus, the influence of the CYP2C9 IVS8-109A>T polymorphism on the losartan MR was evaluated among healthy Ecuadorians. In addition, the frequency of the CYP2C9 IVS8-109A>T polymorphism was determined.nnnRESULTSnAmong CYP2C9-homozygous wild-types, those with the CYP2C9 IVS8-109T/T versus A/A genotypes had a lower MR (p < 0.05). Furthermore, the frequency of the CYP2C9 IVS8-109T variant was lower in Ecuadorians (21.4%; p < 0.001) than in populations from Sweden or Asia (ranging from 32 to 46%).nnnCONCLUSIONnIn this Ecuadorian population, the CYP2C9 IVS8-109T allele was associated with an increased CYP2C9 hydroxylation capacity. Further investigation needs to be carried out in order to clarify the relevance of the SNP of CYP2C9 IVS8-109A>T on losartan hydroxylation across populations and its potential implications in CYP2C9 activity.

Erythrocyte folate content and serum folic acid and homocysteine levels in preeclamptic primigravidae teenagers living at high altitude.

ObjectiveTo measure erythrocyte folate content and serum folic acid and homocysteine (Hcy) levels in preeclamptic primigravidae teenagers living at high altitude.MethodsMeasured analytes were compared to those found in normal teen controls.ResultsTeenagers complicated with preeclampsia displayed significantly lower hematocrit and erythrocyte folic acid levels with higher serum Hcy levels as compared to controls (36.40xa0±xa04.90 vs. 38.99xa0±xa02.89xa0%, 493.80xa0±xa0237.30 vs. 589.90xa0±xa0210.60xa0ng/mL, and 7.29xa0±xa02.52 vs. 5.97xa0±xa01.41xa0μmol/L, respectively, pxa0<xa00.05). There was a non-significant trend for lower serum folic acid levels among preeclampsia teenagers. Serum and erythrocyte folic acid levels positively correlated in preeclampsia teenagers, and levels of both analytes inversely correlated with Hcy levels.ConclusionThis pilot study found that teenagers complicated with preeclampsia living at higher altitude displayed lower erythrocyte folate content in addition to higher serum Hcy levels. More research is warranted to determine the clinical implications of these findings.

Brain structure and function associated with younger adults in growth hormone receptor deficient humans

Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits. SIGNIFICANCE STATEMENT People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive function and brain structure are affected by GHRD. Using MRI, we examined cognition in an Ecuadorian population with GHRD and their unaffected relatives. The GHRD group showed better memory performance than their relatives. The differences in brain structure and function that we saw between the two groups were not consistent with variations typically associated with brain deficits. This study contributes to our understanding of the connection between growth genes and brain aging in humans and provides data indicating that GHR inhibition has the potential to protect against age-dependent cognitive decline.

Maternal plasma and amniotic fluid coenzyme Q10 levels in preterm and term gestations: a pilot study

ObjectiveTo measure maternal plasma and amniotic fluid coenzyme Q10 (CoQ10) levels in preterm and term gestations.Study designThis pilot study comprised a convenience sample of 72 women admitted for labor with singleton live gestations and intact membranes (preterm nxa0=xa027 and term nxa0=xa045).ResultsMedian [interquartile range] maternal plasma CoQ10 levels did not differ among the studied women (preterm, 0.47 [0.12] vs. term, 0.47 [0.23] mmol/L, pxa0=xa00.90). Overall CoQ10 amniotic fluid levels were nearly tenfold lower than those found in maternal plasma, with a significant lower level observed among those delivering preterm (0.050 [0.05] vs. 0.062 [0.04] mmol/L, pxa0=xa00.007). Multiple linear regression analysis controlling for several covariates determined a significant correlation between amniotic fluid CoQ10 levels and neonatal gestational age.ConclusionThis is the first study to assess CoQ10 levels in amniotic fluid during pregnancy in which levels were significantly lower among those delivering preterm. More research is warranted in this regard.

Population pharmacogenetics of Ibero-Latinoamerican populations (MESTIFAR 2014)

MESTIFAR 2014 28-30 November 2014, Panama City, Panama The CEIBA consortium was created within the Ibero-American network of Pharmacogenetics (RIBEF) to study population pharmacogenetics. The current status of these initiatives and results of the MESTIFAR project were analyzed in Panama, 28-30 November 2014. The MESTIFAR project focused on studying CYPs genetic polymorphisms in populations of different ethnic origin. So far, more than 6000 healthy volunteers have been evaluated, making this one of the largest population pharmacogenomic studies worldwide. Three symposia were organized, Pharmacogenetics of indigenous and mestizos populations and its clinical implications, Methodological innovation in pharmacogenetics and its application in health, and General discussion and concluding remarks, about mechanisms and proposals for training, diffusion of pharmacogenetics for Spanish- and Portuguese-speaking health professionals, and bench to bedside pilot projects.

Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives

In the present pandemics of obesity and insulin resistant diabetes mellitus (DM), the specific contribution of etiological factors such as shifts in nutritional and exercise patterns, genetic and hormonal, is subject of ongoing research. Among the hormonal factors implicated, we selected obesity-driven insulin resistance for further evaluation. It is known that growth hormone (GH) has profound effects on carbohydrate metabolism. In consequence, we compared the effects of the lack of the counter-regulatory effects of GH, in a group of subjects with GH receptor deficiency (GHRD) due to a mutated GH receptor vs. that of their normal relatives. It was found that, despite their obesity, subjects with GHRD, have diminished incidence of diabetes, lower glucose and insulin concentrations, and lower values of indexes indicative of insulin resistance such as HOMA-IR. The GHRD subjects were also capable of appropriately handling glucose or mixed meal loads despite diminished insulin secretion. These observations allow us to suggest that the association of obesity with increased risk for diabetes appears to be dependent on intact growth hormone signaling.