Role of secreted frizzled-related protein 4 in prediabetes and type 2 diabetes: a cross sectional study.

BACKGROUND: Type 2 diabetes (T2D) has become an epidemic. Delays in diagnosis and as a consequent late treatment has resulted in high prevalence of complications and mortality. Secreted frizzled-related protein 4 (SFRP4), has been recently identified as a potential early biomarker of T2D related to obesity, due to its association with low grade inflammation in adipose tissue and impaired glucose metabolism. We aimed to evaluate the role of SFRP4 in prediabetes and T2D in a Mexican population. METHODS: This was a cross-sectional study that included 80 subjects with T2D, 50 subjects with prediabetes and 50 healthy individuals. Fasting SFRP4 and insulin concentrations were measured by ELISA. Human serum IL-10, IL-6, IL-1ß and IL-8 levels were quantified by flow cytometry. Genotyping was performed by TaqMan® probes. RESULTS: Prediabetes and T2D patients had significantly higher SFRP4 levels than controls (P < 0.05). In turn, prediabetes subjects had higher SFRP4 concentrations than control subjects (P < 0.05). Additionally, the prediabetes and T2D groups had higher concentrations of proinflammatory molecules such as IL-6, IL-1ß and IL-8, and lower concentrations of IL-10, an anti-inflammatory cytokine, than controls (P < 0.001). The serum SFRP4 concentrations were positively correlated with parameters that are elevated in prediabetes and T2D states, such as, HbA1c and homeostasis model assessment insulin resistance (HOMA-IR), (r = 0.168 and 0.248, respectively, P < 0.05). Also, serum SFRP4 concentrations were positively correlated with concentrations of pro-inflammatory molecules (CRP, IL-6, IL-1ß and IL-8) and negatively correlated with the anti-inflammatory molecule IL-10, even after adjusting for body mass index and age (P < 0.001). The genetic variant rs4720265 was correlated with low HDL concentrations in T2D (P < 0.05). CONCLUSIONS: SFRP4 correlates positively with the stage of prediabetes, suggesting that it may be an early biomarker to predict the risk of developing diabetes in people with high serum concentrations of SFRP4, although further longitudinal studies are required.

Recurrence of Nephrolithiasis and Surgical Events Are Associated with Chronic Kidney Disease in Adult Patients.

Background and objective: Nephrolithiasis (NL) is a public health problem in the population of Southeast Mexico because of its high prevalence and recurrence. The evolution of this pathology can result in renal damage and may even cause chronic kidney disease (CKD), leading to a reduced glomerular filtration rate (GFR), decreased kidney function, and kidney loss in advanced stages. However, few studies support this evidence in the population. The present study aimed to determine risk factors associated with CKD in adult patients in an endemic population of Mexico. Materials and methods: A case-control study was carried out with patients diagnosed with NL. Additionally, the clinical information of patients (age, weight, height, blood pressure, comorbidities, and time of progress of NL), characteristics of the stones (number, location, and Hounsfield units), and biochemical parameters were collected. Results: The recurrence of NL was associated with CKD (OR 1.91; 95% CI 1.37−2.27; p = 0.003). In addition, male sex (p = 0.016), surgical history (p = 0.011), bilateral kidney stones (p < 0.001), and urinary tract infections (p = 0.004) were other factors associated with CKD. Interestingly, thirty-two patients younger than 50 years old with >2 surgical events presented a significant decrease in GFR (p < 0.001). Conclusions: The recurrence of NL and the number of surgical events were risk factors associated with CKD in patients with NL treated in our population.

Shared genetic underpinnings of childhood obesity and adult cardiometabolic diseases.

BACKGROUND: Obesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic traits using a unified statistical approach that integrates pleiotropy and functional annotation data. RESULTS: Pleiotropic genetic effects were significantly abundant in 13 out of 15 childhood BMI-adult cardiometabolic trait tests (P < 3.3 × 10-3). SNPs associated with both childhood BMI and adult traits were more likely to be functionally deleterious than SNPs associated with neither trait. Genetic variants associated with increased childhood obesity tend to increase risk of cardiometabolic diseases in adulthood. We replicated 39 genetic loci that are known to be associated with childhood BMI and adult traits (coronary artery disease, HDL cholesterol, myocardial infarction, triglycerides, total cholesterol, type 2 diabetes, BMI, waist circumference, and waist-to-hip ratio) in previous genome-wide association studies. We also found a novel association of rs12446632 near GPRC5B, which is highly expressed in adipose tissue and the central nervous system, with adult HDL cholesterol. CONCLUSIONS: This study found significant pleiotropic genetic effects and enrichment of functional annotations in genetic variants that were jointly associated with childhood obesity and adult cardiometabolic diseases. The findings provide new avenues to disentangle the genetic basis of life course associations between childhood obesity and adult cardiometabolic diseases.

Whole-exome sequencing in maya indigenous families: variant in PPP1R3A is associated with type 2 diabetes.

It has been presumed that increased susceptibility in Mexicans to type 2 diabetes (T2D) is attributed to the Native American genetic ancestry. Nonetheless, it is not known if there are private genetic variants that confer susceptibility to develop T2D in our population. The Maya indigenous group has the highest proportion of Native American ancestry (98%) which makes it a representative group of the original peoples of Mexico. Thus, the aim of the present study is to identify new genetic variants associated with T2D in Maya families. Whole-exome sequencing was performed on DNA samples from Maya families with a third-generation family history of T2D only in one parental line. Four variants were identified for APOB, PPP1R3A, TPPP2, and GPR1 genes, and were further tested for association with T2D in 600 unrelated Maya in a case-control study. For the first time, rs1799999 in PPP1R3A was associated with risk of T2D in Mayan Mexican individuals (OR = 1.625, P = 0.014). Interestingly, carriers of rs1799999 presented increased values of HOMA-IR. In addition, rs1801702 in APOB was associated with total cholesterol and LDL-C (P = 0.019 and P = 0.020, respectively) in normoglycemic individuals; rs3732083 in GPR1 with HOMA-IR (P = 0.016) and rs9624 in TPPP2 with total cholesterol and triglycerides (P = 0.002 and P = 0.005, respectively) in T2D subjects. Overall, these findings support the idea that there are other genetic variants yet to be described, involved in T2D development in Maya population, being insulin resistance and lipid metabolism the main mechanisms implicated. Thus, these results can contribute to the understanding of diabetes genetic background in Mexican population.

Computed tomographic characterization of urinary stones in patients with urolithiasis from Southeast Mexico.

Urolithiasis (UL) is a severe public health concern in southeastern Mexico. Computed tomography (CT) is the first-line diagnostic method for patients with suspected UL. The present study aimed to characterize stones in the entire urinary system using CT and to contribute to personalized treatment in patients with UL. Patients >18 years of age with suspected UL were enrolled. Characteristics of UL included stone size, location (kidney, ureters, and bladder), composition of the stone in Hounsfield units (HU), presence of staghorn stone(s), and obstructive uropathy. Patients were stratified according to sex and age to determine whether stone size and HU were dependent on hormonal factors in females and on prostatic hyperplasia in males. The Mann-Whitney U test was used to compare median values. Frequencies are expressed as percentages and were analyzed using the Mantel-Haenszel chi-squared test. A total of 1150 patients were included in this study, of whom 744 (64.7 %) had UL in only 1 anatomical location in the urinary system, and 406 (35.3 %) had stones in ≥2 anatomical locations. Localization and stone size differed between males and females (p < 0.05). Additionally, males exhibited differences in HU (p = 0.024) and frequency of obstructive uropathy (p = 0.10) when stratified according to age (≤50 and > 50 years). In addition, females exhibited statistical differences in HU (p = 0.010) and kidney stone size (p = 0.047) dependent on age (≤47 and > 47 years). In conclusion, findings suggest that HU and stone size differ in different anatomical structures of the urinary system. In addition, differences in stone size and composition may be associated with age and sex.

Recovery from ischemic acute kidney injury by spironolactone administration.

BACKGROUND: Prophylactic mineralocorticoid receptor (MR) antagonism with spironolactone (Sp) in rats completely prevents renal damage induced by ischemia. Because acute renal ischemia cannot typically be predicted, this study was designed to investigate whether Sp could prevent renal injury after an ischemic/reperfusion insult. METHODS: Six groups of male Wistar rats were studied: rats that received a sham abdominal operation (S); rats that underwent 20 min of ischemia and reperfusion for 24 h (I/R) and four groups of rats treated with Sp (20 mg/kg) 0, 3, 6 or 9 h after ischemia. RESULTS: As expected, I/R resulted in renal dysfunction characterized by a fall in renal blood flow and glomerular filtration rate and severe tubular injury which was confirmed by a significant increase in tubular damage biomarkers including kidney injury molecule-1, heat shock protein 72 and urinary protein excretion. The renal injury induced by I/R was in part due to Rho-kinase, endothelin and angiotensin II type 1 receptor upregulation. Interestingly, Sp administration at 0 and 3 h after ischemia completely reversed and prevented the damage induced by I/R. The protection induced by Sp given 6 h after ischemia was partial, but no protection was observed by administering Sp 9 h after ischemia. CONCLUSION: Our results show that MR antagonism administered, either immediately or 3 h after I/R, effectively prevented ischemic acute renal injury, indicating that spironolactone is a promising agent for preventing acute kidney injury once an ischemic insult has occurred.

[Is aldosterone a modulator of vascular tone?]. / Es la aldosterona un modulador del tono vascular?

The vascular endothelium is a dynamic tissue that is sensitive to physical and chemical stimuli. The fact that endothelial cells are directly exposed to the blood fluid components provides the ability to regulate diverse physiological functions, among them are: the coagulation, the metabolism of the vascular wall, transcapillary permeability of solutes and water, and the vascular tissue remodeling. In addition to these functions, the vascular endothelium plays a major role in local regulation and maintenance of vascular tone. This function is performed by the release of vasoactive factors such as, nitric oxide, endothelin-1, angiotensin-II, adenosine, prostacyclins, thromboxanes, free radicals, among other compounds not less important. Recent studies have suggested a new player in the control of vascular tone: the aldosterone. Thus, the recent evidence suggests that this mineralocorticoid hormone may cause vasoconstriction in pathophysiological conditions, through modulating the gene expression and activity of endothelin-1, glucose 6 phosphate deshydrogenase and Rho kinase, as well as by altering the phosphorylation and activity of endothelial nitric oxide synthase (eNOS). It has also been observed involvement of aldosterone in the generation of oxidative stress, action exerted indirectly through reduction of the bioavailability of nicotinamide adenine dinucleotide phosphate (NADPH). Therefore, this review focuses on describing some of the mechanisms involved in the regulation of vascular tone and review studies that show recent evidence of the role of aldosterone as a mediator of this function.

Risk factors associated with diabetic neuropathy in Mexican patients.

INTRODUCTION: Diabetic neuropathy (DN) is one of the most common complications of type 2 diabetes (T2D) and is a leading cause of lower limb amputation. The aim of the present study was to evaluate the risk factors contributing to DN in Mexican patients through the comparison of T2D patients with and without DN. MATERIALS AND METHODS: This cross-sectional study consisted of 509 subjects from Mexico who were classified as with DN and without DN. DN was assessed according to Douleur Neuropathique 4 questionnaire. Logistic regression analysis was performed to analyze risk factors contributing to DN. RESULTS: The prevalence of DN in the studied population was 28.3%. The risk factors associated with DN were T2D duration (odds ratio [OR]: 2.51; 95% confidence interval [CI] 1.36-4.65), glycemic exposure index (OR: 1.82; 95% CI 1.01-3.64), low- and high-density lipoprotein levels (OR: 1.53; 95% CI 1.02-2.31), metformin treatment (OR: 2.08; 95% CI 1.11-3.91), diabetic retinopathy (OR: 1.65; 95% CI 1.07-2.54), and smoking (OR: 1.51; 95% CI 1.00-2.26). CONCLUSIONS: Therefore, the early identification of risk factors for DN development in Mexican population would allow implementing personalized strategies to improve the overall T2D patients' quality of life and reduce healthcare costs in our country.

ANTECEDENTES: La neuropatía diabética (ND) es una de las complicaciones más comunes de la diabetes tipo 2 (DT2). ­. OBJETIVO: Investigar los factores de riesgo que contribuyen al desarrollo de ND en población mexicana con DT2, comparando pacientes diabéticos con y sin ND. MÉTODO: Estudio transversal con 509 pacientes mexicanos con DT2, clasificados en dos grupos, con y sin ND. La ND fue diagnosticada con el cuestionario DN4. La identificación de los factores de riesgo de ND se realizó mediante un análisis de regresión logística. RESULTADOS: La prevalencia de ND en la población de estudio fue del 28.3%. Los factores de riesgo asociados a ND fueron la duración de la DT2 (odds ratio [OR]: 2.51; intervalo de confianza del 95% [IC 95%]: 1.36-4.65), el índice glucémico (OR: 1.82; IC 95%: 1.01-3.64), las concentraciones bajas de colesterol unido a lipoproteínas de alta densidad (OR: 1.53; IC 95%: 1.02-2.31), el tratamiento con metformina (OR: 2.08; IC 95%: 1.11-3.91), la retinopatía diabética (OR: 1.65; IC 95%: 1.07-2.54) y el tabaquismo (OR: 1.51; IC 95%: 1.00-2.26). CONCLUSIONES: La identificación temprana de los factores de riesgo para el desarrollo de ND en población mexicana permitirá implementar estrategias personalizadas para mejorar la calidad de vida de los pacientes con DT2 y disminuir el gasto del sector salud originado por esta complicación.

Polymerized type I collagen reduces chronic cyclosporine nephrotoxicity.

BACKGROUND: Polymerized type I collagen (P-collagen) has been successfully used to reduce human hypertrophic scars due to its anti-fibrotic and anti-inflammatory properties. We therefore carried out a study to determine if P-collagen reduces functional and structural injury in chronic cyclosporine [cyclosporine A (CsA)] nephropathy. METHODS: Four groups of six male Wistar rats fed with a low sodium diet were treated with vehicle, P-collagen (0.8 mg/day, i.p.), CsA (15 mg/kg) or CsA + P-collagen for 15 days. Mean arterial pressure, renal blood flow and glomerular filtration rate were measured in all groups. Structural injury such as arteriolopathy, tubulo-interstitial fibrosis (TI-fibrosis) and positive apoptotic cells were quantified. The mRNA expression levels of transforming growth factor-beta (TGF-beta), kidney injury molecule (Kim-1), alpha-smooth muscle actin (alpha-SMA), glutathione peroxidase, catalase and Cu/Zn superoxide dismutase (SOD) as well as MnSOD were assessed. Antioxidant enzyme activity, renal lipoperoxidation and urinary excretion of oxygen peroxide (UH(2)O(2)V) were determined. RESULTS: Cyclosporine produced renal dysfunction and induced the development of arteriolopathy, TI-fibrosis and tubular apoptosis. These alterations were associated with increases in TGF-beta, Kim-1 and alpha-SMA mRNA levels as well as with a significant increase of oxidative stress and a reduction of SOD activity. P-Collagen partially ameliorated CsA-induced renal dysfunction and structural injury and prevented both tubular apoptosis and increased oxidative stress. This renoprotective effect was found to be associated with a reduction of TGF-beta, Kim-1 and alpha-SMA mRNA levels. CONCLUSIONS: This study has therefore demonstrated that P-collagen appears to have anti-fibrotic and anti-apoptotic properties and highlights the possibility that the compound might be useful in a strategy to reduce chronic CsA nephrotoxicity.

Pharmacogenetic Evaluation of Metformin and Sulphonylurea Response in Mexican Mestizos with Type 2 Diabetes.

BACKGROUND: In Mexico, approximately 25% of patients with type 2 diabetes (T2D) have adequate glycemic control. Polymorphisms in pharmacogenetic genes have been shown to have clinical consequences resulting in drug toxicity or therapeutic inefficacy. OBJECTIVE: The study aimed to evaluate the impact of variants in genes known to be involved in response to oral hypoglycemic drugs, such as CYP2C9, OCT, MATE, ABCA1 and C11orf65, in the Mexican Mestizo population of T2D patients. METHODS: In this study, 265 patients with T2D were enrolled from the Hospital Juárez de México, Mexico City. Genotyping was performed by TaqMan® assays. SNP-SNP interactions were analyzed using the multifactor dimensionality reduction (MDR) method. RESULTS: Carriers of the del allele of rs72552763 could achieve better glycemic control than noncarriers. There was a significant difference in plasma glucose and HbA1c levels among rs622342 genotypes. The results suggested an SNP-SNP interaction between rs72552763 and rs622342 OCT1 and rs12943590 MATE2. CONCLUSION: The interaction between rs72552763 and rs622342 in OCT1, and rs12943590 in MATE2 suggested an important role of these polymorphisms in metformin response in T2D Mexican Mestizo population.

Metabolic syndrome in Mexican children: Low effectiveness of diagnostic definitions. / Síndrome metabólico en niños mexicanos: poca efectividad de las definiciones diagnósticas.

BACKGROUND: Early identification of children with metabolic syndrome (MS) is essential to decrease the risk of developing diabetes and cardiovascular disease in adulthood. Detection of MS is however challenging because of the different definitions for diagnosis; as a result, preventive actions are not taken in some children at risk. The study objective was therefore to compare prevalence of MS in children according to the IDF, NCEP-ATP-III, Cook, de Ferranti and Weiss definitions, considering insulin resistance (IR) markers such as HOMA-IR and/or metabolic index (MI). METHODS: A total of 508 Mexican children (aged 9 to 13 years) from seven schools were enrolled in a cross-sectional study. Somatometric, biochemical, and hormonal measurements were evaluated. RESULTS: Frequency of MS was 2.4-45.9% depending on the definition used. Frequency of IR in children not diagnosed with MS was 12.4-25.2% using HOMA-IR and 4.0-16.3% using MI. When HOMA-IR or MI was included in each of the definitions, frequency of MS was 8.5-50.2% and 7.7-46.9% respectively. The kappa value including HOMA-IR and/or MI was greater than 0.8. CONCLUSIONS: This study demonstrated the poor effectiveness of the current criteria used to diagnose MS in Mexican children, as shown by the variability in the definitions and by the presence of IR in children who not diagnosed with MS. Inclusion of HOMA-IR and/or MI in definitions of MS (thus increasing agreement between them) decreases the chance of excluding children at risk and allows for MS prevalence between populations.

Genetic Component of Type 2 Diabetes in a Mexican Population.

Type 2 diabetes (T2D) is a complex disease caused by the interaction of genetic and environmental factors. In this regard, it has been demonstrated that Hispanics have a greater susceptibility to developing complex diseases like T2D, which has been attributed to their Amerindian component. Mexico has a wide population variety as a result of Amerindian (56-69%), European (26-41.8%) and African (1.8-6%) ancestral components. The stratification of the population has made difficult the study of T2D in the Mexican population. Despite advances, in Mexico the studies in this field are scarce; 9 of 88 loci associated with type 2 diabetes by genome-wide association studies (GWAS) in Caucasian populations have been replicated in the Mexican population. Currently, only 19 common variants and two variants of low frequency have been associated with T2D in Mexico. With respect to the private genetic variation in Mexican population, only one haplotype and two genetic variants have been described. This confirms the existence of new genetic variants not yet described, exclusive to the Mexican population, which suggests most likely, that there are more genetic variants to discover. Thus, in the present review we aim to bring together in one place all the studies about T2D in Mexico to understand the contribution of the genetic factors in the susceptibility to developing T2D in a Mexican population.

Genetic variability of CYP2C9*2 and CYP2C9*3 in seven indigenous groups from Mexico.

AIM: CYP2C9 is one of the major drug metabolizing enzymes, however, little is known about polymorphisms in CYP2C9 gene and pharmacological implications in Mexican indigenous populations. Thus, frequencies of CYP2C9*2 and CYP2C9*3 alleles were evaluated in indigenous groups located in northwest (Cora), center (Mazahua and Teenek), south (Chatino and Mixteco) and southeast (Chontal and Maya) regions Mexico. MATERIALS & METHODS: Allelic discrimination was performed by real-time PCR. RESULTS: CYP2C9*2 allele was found only in Chontal and Maya groups, despite the low contribution of Caucasian component in these populations. CYP2C9*3 allele was present in all populations except in Mazahua, showing a wide genetic variability in the studied populations. Interestingly, we found significant differences between indigenous groups in CYP2C9*3 allele, even in groups located at the same region and belonging to the same linguistic family. CONCLUSION: These results contribute to laying the pharmacogenetic bases in Mexico, in addition to improving treatment, taking into account the genetic interethnic differences.