Arterial Stiffness and HbA1c: Association Mediated by Insulin Resistance in Hispanic Adults.

Arterial stiffness may be associated with glucose metabolism parameters, such as HbA1c, mainly via insulin resistance. We aimed to investigate the association between arterial stiffness and HbA1c and explore the mediator effect of insulin resistance. In this cross-sectional study, arterial stiffness (pulse-wave velocity; PWV), HbA1c, and insulin resistance (METS-IR) were determined in Hispanic adults. In addition to sex and age, various biochemical measurements (glucose, lipid profile, etc.) and adipose tissue (fat mass and visceral fat mass) were considered as potential confounding variables. A multivariate regression analysis shows that HbA1c is associated with PWV, even after adjusting for several confounding variables. Importantly, the results show that insulin resistance mediated 17.9% of the effect of HbA1c over PWV. In conclusion, HbA1c may be a potential resource for predicting arterial stiffness due to the influence of insulin resistance in Hispanic subjects.

Association between insulin resistance and arterial stiffness in Mexican patients without type 2 diabetes.

BACKGROUND: Central aortic arterial stiffness (CAAS) is an independent cardiovascular risk factor. Insulin resistance (IR) contributes to CAAS-associated risk. OBJECTIVE: To evaluate the association between IR and CAAS in a Mexican population without diabetes. METHODS: IR was estimated with Homeostatic Model Assessment 2-Insulin Resistance (HOMA2-IR) and other surrogate markers (Metabolic score for IR [METS-IR], Quantitative Insulin Sensitivity Check Index [QUICKI], triglycerides/glucose index [TyG], TyG*body mass index [TyG*BMI] and triglycerides/high-density lipoprotein cholesterol ratio [TG/HDL-C]). CAAS was evaluated using carotid-femoral pulse wave velocity analysis (PWVcf) and the standardized augmentation index (AI-75). Bivariate correlations were made between surrogate markers and PWVcf. Increased CAAS was defined as PWVcf above the 90th percentile. Thresholds and area under the curve (AUC) were obtained for each surrogate marker in order to evaluate their performance in estimating increased CAAS. RESULTS: Three hundred and fifty-eight patients were included. A correlation was found between HOMA2-IR and PWVcf; this correlation was replicated with other surrogate markers. METS-IR and TyG*BMI had the highest degree of correlation with PWVcf. When adjustments were made for covariates, the correlations with TyG*BMI, METS-IR, HOMA2-IR and QUICKI maintained significance. HOMA2-IR showed the strongest correlation with AI-75. METS-IR and TyG showed the best AUC. Patients with prediabetes had the highest PWVcf. CONCLUSIONS: The relationship between IR and CAAS is present before the onset of diabetes; this association may entail higher cardiovascular risk.

ANTECEDENTES: La rigidez arterial central aórtica (RACA) es un factor de riesgo cardiovascular independiente. La resistencia a la insulina (RI) contribuye al riesgo asociado a RACA. OBJETIVO: Evaluar la asociación entre RI y RACA en una población mexicana sin diabetes. MÉTODOS: La RI se estimó con HOMA2-IR y (Homeostatic Model Assessment 2-Insulin Resistance) otros subrogados (METS-IR [Metabolic score for IR], QUICKI [Quantitative Insulin Sensitivity Check Index], TyG [ratio triglicéridos/glucosa], TyG*IMC [TyG*índice de masa corporal] y TG/HDL [ratio TG/lipoproteínas de alta densidad]). Se evaluó la RACA mediante el análisis de velocidad de onda del pulso carotídeo-femoral (VOPcf) y el índice de aumentación estandarizado (AI-75). Se realizaron correlaciones bivariante entre los subrogados y la VOPcf. RACA aumentada se definió como VOPcf arriba del percentil 90. Se obtuvieron puntos de corte y área bajo la curva (ABC) para cada subrogado para estimar RACA aumentada. RESULTADOS: Se incluyó 358 pacientes. Se encontró una correlación entre HOMA2-IR y VOPcf; esta correlación se replicó con los subrogados. METS-IR y TyG*IMC tuvieron el mayor grado de correlación con VOPcf. Al ajustar, las correlaciones con TyG*IMC, METS-IR, HOMA2-IR y QUICKI mantuvieron significancia. La correlación con AI-75 fue mayor para HOMA2-IR. METS-IR y TyG mostraron la mejor ABC. Los pacientes con prediabetes tuvieron mayor VOPcf. CONCLUSIONES: La relación entre la RI y la RACA está presente desde etapas no diabéticas; esta asociación puede conllevar mayor riesgo cardiovascular.

Intermittent Fasting as Part of the Management for T2DM: from Animal Models to Human Clinical Studies.

PURPOSE OF REVIEW: Diet is a pillar of type 2 diabetes mellitus (T2DM) management. Intermittent fasting (IF) is postulated as a novel approach, able to improve glucose control and potentially capable of reversing some of the pathophysiological alterations of this condition. In this review, the molecular and clinical evidence of diets based on intermittent energy restriction (IER) in laboratory animal models and subjects with type 2 diabetes is discussed. The mechanisms through which IF are thought to improve glucose homeostasis and reverse ß cell failure are also reviewed. RECENT FINDINGS: Studies derived from murine models suggest that IER is associated with improvements in ß cell function and insulin resistance. Two main mechanisms have been demonstrated, one derived from the autophagy-lysosome pathway and, the other from an increase in neurogenin3 (Ngn3) levels (a marker for endocrine progenitor cells like ß cells during development). Notably, IER also promotes reconstruction of gut microbiota. In mice, all effects were independent of weight loss. By contrast, in human studies, outcomes are widely attributable to weight loss. The more consistent results are reductions in body weight, visceral fat, and glucose and insulin levels. Increases in HDL cholesterol levels are also frequently reported. The decrease in insulin levels observed in humans is in opposition with the increase reported in mice, suggesting that the main mechanism in humans is an improvement in peripheral insulin action. Recommending diets based on intermittent fasting in humans is based on the promising results found in animal models where an improvement in ß cell function has been recorded. ß cell function after IF has not been assessed in human subjects with T2DM. This review provides information regarding different protocols for the implementation of IF in diabetic persons and also provides important safety advice in order to avoid adverse effects. Clinical studies do not show an increased risk of hypoglycemia, and a recent case series reported reversal of T2DM.

Contribution of Known Genetic Risk Variants to Dyslipidemias and Type 2 Diabetes in Mexico: A Population-Based Nationwide Study.

Dyslipidemias are common risk factors for the development of chronic disorders including type 2 diabetes (T2D). Over 100 associated loci have been identified but few reports have evaluated the population attributable fraction captured by them in population-based nationwide surveys. Therefore, we determined the population contribution of a set of known genetic risk variants to the development of dyslipidemias and T2D in Mexico. This study included 1665 participants from a Mexican National Health Survey carried out in the year 2000. It is a probabilistic complex sample survey of households, which comprises representative data at a national level. 103 previously reported SNPs associated with different dyslipidemias or T2D were genotyped and used to compute polygenic risk scores. We found that the previously known variants associated with dyslipidemias explain at most 7% of the total risk variance of lipid levels. In contrast, the known genetic risk component for T2D explained a negligible amount of variance (0.1%). Notably, variants derived from the Native-American ancestry have the strongest effect and contribute with a high proportion of the variance. These results support the need for additional studies aimed to identify specific genetic risk variants for Mexican population.

Prediction of incident hypertension and arterial stiffness using the non-insulin-based metabolic score for insulin resistance (METS-IR) index.

Hypertension is associated with insulin resistance (IR), metabolic syndrome (MS), and arterial stiffness. Non-insulin-based IR indexes were developed as tools for metabolic screening. Here, we aimed to evaluate the novel non-insulin-based Metabolic Score for IR (METS-IR) index for the prediction of incident hypertension and arterial stiffness evaluated using pulse wave velocity (PWV) analysis, compared with other non-insulin-based IR indexes. We evaluated two populations, a cross-sectional evaluation of high-risk individuals (n = 305) with a wide range of metabolic comorbidities and dyslipidemia in whom PWV measurement was performed and a 3-year prospective cohort of normotensive individuals (N = 6850). We observed a positive correlation between METS-IR and PWV in the cross-sectional cohort, which was higher compared with other non-insulin-based fasting IR indexes; furthermore, PWV values >75th percentile were associated with the upper tercile of METS-IR values. In the prospective cohort, we observed an increased risk for incident hypertension for the upper METS-IR tercile (METS-IR ≥ 46.42; HR: 1.81, 95% CI: 1.41-2.34), adjusted for known cardiovascular risk factors, and observed that METS-IR had greater increases in the predictive capacity for hypertension along with SBP and the Framingham Hypertension Risk Prediction Model compared with other non-insulin-based IR indexes. Therefore, METS-IR is a novel non-insulin-based IR index which correlates with arterial stiffness and is a predictor of incident hypertension, complementary to previously validated risk prediction models.

Development and validation of a predictive model for incident type 2 diabetes in middle-aged Mexican adults: the metabolic syndrome cohort.

BACKGROUND: Type 2 diabetes mellitus (T2D) is a leading cause of morbidity and mortality in Mexico. Here, we aimed to report incidence rates (IR) of type 2 diabetes in middle-aged apparently-healthy Mexican adults, identify risk factors associated to ID and develop a predictive model for ID in a high-risk population. METHODS: Prospective 3-year observational cohort, comprised of apparently-healthy adults from urban settings of central Mexico in whom demographic, anthropometric and biochemical data was collected. We evaluated risk factors for ID using Cox proportional hazard regression and developed predictive models for ID. RESULTS: We included 7636 participants of whom 6144 completed follow-up. We observed 331 ID cases (IR: 21.9 per 1000 person-years, 95%CI 21.37-22.47). Risk factors for ID included family history of diabetes, age, abdominal obesity, waist-height ratio, impaired fasting glucose (IFG), HOMA2-IR and metabolic syndrome. Early-onset ID was also high (IR 14.77 per 1000 person-years, 95%CI 14.21-15.35), and risk factors included HOMA-IR and IFG. Our ID predictive model included age, hypertriglyceridemia, IFG, hypertension and abdominal obesity as predictors (Dxy = 0.487, c-statistic = 0.741) and had higher predictive accuracy compared to FINDRISC and Cambridge risk scores. CONCLUSIONS: ID in apparently healthy middle-aged Mexican adults is currently at an alarming rate. The constructed models can be implemented to predict diabetes risk and represent the largest prospective effort for the study metabolic diseases in Latin-American population.

The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-size adipocytes.

Objective A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk. Design Cross-sectional study. Methods We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic-hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies. Results Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (ß = -0.164, P = 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P = 0.02) and of 7.34 U/L in gamma-glutamyltransferase (GGT) (P = 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P < 0.001). Conclusions Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.

Cholesterol efflux capacity of large, small and total HDL particles is unaltered by atorvastatin in patients with type 2 diabetes.

BACKGROUND AND AIMS: Research on the biologic activities of HDL, such as cholesterol efflux capacity and HDL composition, has allowed the understanding of the effect of interventions directed to improve cardiovascular risk. Previously, statin therapy has shown conflicting results about its effects on cholesterol efflux capacity of HDL; the underlying mechanisms are unclear but studies with positive effects are associated with an increase of HDL-cholesterol levels. We investigated if 10 weeks of atorvastatin therapy changes HDL efflux capacity and the chemical composition of its subpopulations. METHODS: In a before-after design basis, HDL-cholesterol levels, chemical composition and cholesterol efflux capacity from HDL subpopulations isolated by isophynic ultracentrifugation were assessed in plasma samples from 60 patients with type 2 diabetes mellito (T2DM) at baseline and after 10 weeks of treatment with 20 mg atorvastatin. Cholesterol efflux was measured from human THP-1 cells using large, light HDL2b and small, dense 3c subpopulations as well as total HDL as acceptors. Changes of cholesterol efflux and chemical composition of HDL after treatment were analyzed. Correlations among variables potentially involved in cholesterol efflux were evaluated. RESULTS: A significant decrease of 4% in HDL-cholesterol levels was observed from 47 (42-54) to 45 (39-56) mg/dL, p = 0.02. Cholesterol efflux from total-HDL and HDL2b and 3c subfractions was maintained unchanged after treatment. The total mass of HDL remained unaffected, except for the HDL3a subpopulation accounted for by a significant increase in total protein content. No significant correlations for variables previously known to be associated with cholesterol efflux were found in our study. CONCLUSIONS: Short therapy of 10 weeks with 20 mg of atorvastatin does not modify the cholesterol efflux capacity neither the total mass of HDL2b, HDL3c and total HDL. The discrepancy with previous reports may be due to the selective effects among different classes of statins or differences in the approaches to measure cellular cholesterol efflux.

Identification of a threshold to discriminate fasting hypertriglyceridemia with postprandial values.

BACKGROUND: Postprandial lipemia is an important cardiovascular risk factor. The assessment of postprandial lipid metabolism is a newly trend that several consortiums and countries have adopted. The aim of the study is to determine a postprandial triglyceride concentration cut-off point that accurately discriminate individuals with fasting normal triglyceride concentrations from those with fasting hypertriglyceridemia. METHODS: Cross sectional population-based study. A total of 212 subjects underwent an eight hours' oral fat tolerance test. Samples were taken fasting, three, four, five, six and eight hours after the meal. The area under the receiver operating characteristic curve (c-statistic) was computed using postprandial triglycerides concentrations as independent predictor, and fasting hypertriglyceridemia as dependent variable. RESULTS: The best threshold of postprandial lipemia to discriminate fasting hypertriglyceridemia was 280 mg/dL at any hour area under the curve 0.816 (95% confidence interval 0.753-0.866), bootstrap-corrected c-statistic = 0.733 (95% confidence interval 0.68-0.86). The same value was compared with apolipoprotein B concentrations (>90th percentile) having a good performance: area under the curve 0.687 95% confidence interval 0.624-0.751). Likewise, subjects with high postprandial lipemia have higher Globo risk scores. CONCLUSION: The 280 mg/dL cut-off point value of postprandial triglycerides concentration any time after a test meal discriminate subjects with fasting hypertriglyceridemia. This threshold has a good performance in a heterogeneous population and has a good concordance with cardiovascular risk surrogates.

Mexican Carriers of the HNF1A p.E508K Variant Do Not Experience an Enhanced Response to Sulfonylureas.

OBJECTIVE: To assess whether an ethnic-specific variant (p.E508K) in the maturity-onset diabetes of the young (MODY) gene hepatocyte nuclear factor-1α (HNF1A) found in Mexicans is associated with higher sensitivity to sulfonylureas, as documented in patients with MODY3. RESEARCH DESIGN AND METHODS: We recruited 96 participants (46 variant carriers and 50 age- and sex-matched noncarriers). Response to glipizide (one 2.5-5.0-mg dose), metformin (four 500-mg doses), and an oral glucose challenge was evaluated using a previously validated protocol. Glucose and insulin levels and their areas under the curve (AUCs) were compared between groups. RESULTS: Carriers of the p.E508K variant had a lower maximum insulin peak during the glipizide challenge as compared with noncarriers with diabetes (P < 0.05). Also, carriers had a lower insulin response after the oral glucose challenge. Following an oral glucose tolerance test in the presence of metformin, carriers of the p.E508K variant with diabetes had a lower maximum insulin peak and total and incremental insulin AUC value as compared with noncarriers with diabetes (P < 0.05). A similar but nonsignificant trend was seen in participants without type 2 diabetes. CONCLUSIONS: Carriers of variant p.E508K in HNF1A have a reduced insulin response rather than the increased sensitivity to sulfonylureas seen in patients with MODY3.

[Matricaria chamomilla (aqueous extract) improves atopic dermatitis-like lesions in a murine model]. / Matricaria chamomilla (extracto acuoso) induce mejoría en lesiones tipo-dermatitis atópica en un modelo murino.

BACKGROUND: Matricaria Chamomilla L. (Mch), popularly known as chamomile, has been used for centuries as an herbolary remedy due to its broad clinical spectrum. The aim of this study was to evaluate the effect of Mch associated to a vehicle with emollient function in induced atopic dermatitis (AD)-like lesions in a murine model. METHODS: AD was induced with dinitrochlorobenzene on 12 male seven-week old BALB/c mice. Animals were divided in three groups (control, GC; control negative, GCN; and experimental, GE). Liquid petrolatum was applied to the GCN and liquid petrolatum with aqueous extract of Mch at 7% to the GE. Induction and evolution of the lesions were verified by biopsy at 2nd and 6th week. Evaluation of peripheral blood cells to correlate inflammatory cells was made as well at the same weeks. Lesions were clinically evaluated at 2nd, 4th and 6th week. Scratching was monitored according to the observation methodology of Kobayashi et al. RESULTS: Mch aqueous extract associated to a vehicle with emollient function improves atopic dermatitis-like lesions after two weeks.

INTRODUCCIÓN: Matricaria chamomilla L. (Mch), conocida popularmente como manzanilla, ha sido utilizada por cientos de años como remedio herbolario debido a su amplio espectro en cuanto a sus usos clínicos. El objetivo de este trabajo fue evaluar el efecto de Mch asociada a un vehículo con función emoliente como tratamiento de lesiones tipo-dermatitis atópica (DA) en un modelo murino. MÉTODOS: se indujo DA con dinitroclorobenceno a 12 ratones BALB/c macho de siete semanas de edad, divididos en tres grupos (control, GC; control negativo, GCN y; experimental, GE). Se aplicó petrolato líquido al GCN y petrolato líquido con extracto acuoso de Mch al 7% al GE durante cuatro semanas. La inducción y evolución de las lesiones se corroboraron por biopsia a las dos y seis semanas, analizando sangre periférica en búsqueda de células inflamatorias en los mismos tiempos. Las lesiones fueron evaluadas clínicamente a las dos, cuatro y seis semanas. El rascado se evaluó de acuerdo a la metodología de observación de Kobayashi et al. RESULTADOS: el extracto acuoso liofilizado de Mch asociado a un vehículo con función emoliente demostró mejoría del aspecto de las lesiones tipo DA después de dos semanas.

A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.

Factors associated with postprandial lipemia and apolipoprotein A-V levels in individuals with familial combined hyperlipidemia.

BACKGROUND: Alterations in postprandial metabolism have been described in familial combined hyperlipidemia (FCH); however, their underlying mechanisms are not well characterized. We aimed to identify factors related to the magnitude of postprandial lipemia and apolipoprotein (apo) A-V levels in subjects with FCH. METHODS: FCH cases (n = 99) were studied using a standardized meal test. Abdominal obesity was assessed using the waist to hip ratio (WHR). A linear regression model was performed to investigate the variables associated with the triglycerides incremental area under the curve (iAUC). Independent associations between metabolic variables and apo A-V iAUC were also investigated in a randomly selected subgroup (n = 44). The study sample was classified according to the presence of fasting hypertriglyceridemia (≥150 mg/dL) and abdominal obesity (WHR ≥0.92 in men and ≥0.85 in women) to explore differences in parameters. RESULTS: The fasting apo B-48 levels (r = 0.404), and the WHR (r = 0.359) were independent factors contributing to the triglycerides iAUC (r2 = 0.29, P < 0.001). The triglycerides iAUC was independently associated with the apo A-V iAUC (r2 = 0.54, P < 0.01). Patients with both hypertriglyceridemia and abdominal obesity showed the most robust triglycerides and apo A-V postprandial responses. CONCLUSIONS: In patients with FCH the fasting apo B-48 level is the main factor associated with postprandial lipemia. Abdominal obesity also contributes to the magnitude of the postprandial response.The triglycerides postprandial increment is the principal factor associated with the apo A-V postprandial response.

Treatment of metabolic syndrome slows progression of diabetic nephropathy.

BACKGROUND: Metabolic syndrome contributes to the development of albuminuria and to the decrease of glomerular filtration rate (GFR) in type 2 diabetes patients. The aim of this study was to analyze the effect of MS treatment on the progression of diabetic nephropathy (DN). METHODS: This was a retrospective and comparative cohort study. Baseline and follow-up data related to the presence of metabolic syndrome, microalbuminuria (mA), and GFR were obtained in individuals with type 2 diabetes. Subjects were classified in two groups: (1) With correction of metabolic syndrome and (2) without correction of metabolic syndrome at follow-up. Furthermore, they were stratified in four subgroups: (A) Without metabolic syndrome at baseline and at follow-up, (B) with metabolic syndrome and correction of metabolic syndrome, (C) without metabolic syndrome and development of metabolic syndrome, and (D) with metabolic syndrome and persistence of metabolic syndrome. RESULTS: Final GFR and mA were lower and higher, respectively, in group 2 versus 1 [89.8±3 2.3 vs. 98.3±32.0 mL/min, P=0.010, and 51.0 (13.5-195) vs. 7.9 (4-31) mg/day, P<0.001, respectively]. Lack of metabolic syndrome correction [hazard ratio (HR)=2.8, 95% confidence interval (CI) 1.9-4.2, P<0.001], being in subgroups C (HR=2.05, 95% CI 1.03-4.1, P=0.04) and D (HR=3.3, 95% CI 2.0-5.3, P<0.001), and the presence of two (HR=3.4, 95% CI 1.9-6.1, P<0.001), three (HR=5.0, 95% CI 2.5-9.9, P<0.001), and four (HR=4.2, 95% CI 1.5-12.1, P=0.006) metabolic syndrome components were independent factors associated with development of mA in Cox regression analysis adjusted for age, gender, baseline mA and GFR, glycosylated hemoglobin (HbA1c), hypertension, and obesity. CONCLUSIONS: Metabolic syndrome treatment and control are independently associated with a lesser progression of DN.