Cristina Revilla-Monsalve

Association of a Low-Frequency Variant in HNF1A With Type 2 Diabetes in a Latino Population

IMPORTANCE Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

Prediabetes and its relationship with obesity in Mexican adults: The Mexican Diabetes Prevention (MexDiab) Study.

BACKGROUND Epidemiological data on impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) based on a representative Mexican sample are not available; thus, the objectives of this study were to determine the prevalence and distribution of IFG and IGT, and to establish its relationship with obesity in Mexican adults. METHODS We performed a cross-sectional population-based study on a representative sample of Mexican adults aged 30 to 65 years. Anthropometric measurements of obesity that included waist circumference (WC) and total body fat percentage were collected and the body mass index calculated. All subjects also underwent an oral glucose tolerance test. Diagnosis of glucose metabolism disorders was based on criteria of the American Diabetes Association. RESULTS Prevalence of IFG, IGT, and IFG+IGT was 24.6%, 8.3%, and 10.3%, respectively. The age-adjusted prevalence of IFG (49.5% and 50.5%), IGT (49.1% and 50.9%), and IFG+IGT (57.3% and 42.7%) was similar in men and women. Prevalence of obesity was 45.9% with predominance in women (48.8% versus 42.1%, P = 0.01). A total of 394 (31.0%) individuals were overweight. Among the 550 prediabetic normal weight subjects, 70 (22.4%), 15 (14.2%), and 7 (5.3%) had IFG, IGT, or IFG+IGT. The odds ratio (OR) between WC and IFG (OR 3.1, CI(95%) 1.4-9.7), IGT (OR 3.2, CI(95%) 1.2-9.1), and IFG+IGT (OR 2.8, CI(95%) 1.3-8.2) was higher than the OR of other measurements of obesity. CONCLUSIONS Prevalence of prediabetes in the Mexican adult population is high. WC is the measure of obesity more strongly associated with metabolic glucose disorders. A high proportion of subjects with normal weight exhibit prediabetes.

Efficacy of glimepiride/metformin combination versus glibenclamide/metformin in patients with uncontrolled type 2 diabetes mellitus ☆

AIM The aim of this study was to compare the efficacy of glimepiride/metformin combination versus glibenclamide/metformin for reaching glycemic control in patients with uncontrolled type 2 diabetes mellitus. PATIENTS AND METHODS A randomized, double-blind, multicenter clinical trial was performed in 152 uncontrolled type 2 diabetic patients. Serum fasting and postprandial glucose, hemoglobin A1c (A1C), high-density lipoprotein cholesterol, and triglycerides were measured. After random allocation, all patients received two pills of glimepiride (1 mg)/metformin (500 mg) or glibenclamide (5 mg)/metformin (500 mg) po once a day. Dosage was increased to a maximum of four pills in order to reach the glycemic control goals (fasting glucose <or=7.2 mmol/l, postprandial glucose <10.0 mmol/l, A1C <7%, or an A1C >or=1% reduction). Statistical analyses were carried out using chi-square, ANOVA, or Students t test. The protocol was approved by an ethics committee and met all requirements needed to perform research in human subjects; all patients gave written informed consent. RESULTS Each study group included 76 patients. No significant differences in basal clinical and laboratory characteristics between groups were found. At the end of the study, A1C concentration was significantly lower in the glimepiride/metformin group (P=.025). A higher proportion of patients from the glimepiride group (44.6% vs. 26.8%, P<.05) reached the goal of A1C <7% at 12 months of treatment. A higher proportion of hypoglycemic events were observed in the glibenclamide group (28.9% vs. 17.1%, P<.047). CONCLUSION Glimepiride/metformin demonstrated being more efficacious than glibenclamide/metformin at reaching the glycemic control goals with less hypoglycemic events in patients with uncontrolled type 2 diabetes mellitus.

Cardiovascular Risk Factors and Acculturation in Yaquis and Tepehuanos Indians from Mexico

BACKGROUND Cardiovascular (CV) risk factors are influenced by behavioral, cultural, and social factors, suggesting that acculturation plays a significant role in the emergency and growth of chronic disease. The objective of this study was to determine the relation between CV risk factors and the main components of acculturation, in Yaquis and Tepehuanos Indians from Mexico. METHODS This was a cross-sectional population-based study in Yaquis and Tepehuanos communities from the Yaqui Valley in Sonora and the Sierra Madre Occidental Mountains in Durango, in northwest Mexico. Acculturation status is different in both ethnic groups, with Tepehuanos living in small and remote communities retaining their traditional lifestyle and Yaquis living in well-communicated communities that have assumed Westernized lifestyles. RESULTS A total of 278 indigenous (120 Tepehuanos and 158 Yaquis) were randomly enrolled. Prevalence of obesity (48.1 and 6.7%, p <0.001), diabetes (18.3 and 0.83%, p <0.001), hypertriglyceridemia (43.0 and 15.0%, p <0.001), alcohol consumption (46.8 and 26.6%, p >0.001), and smoking (29.7 and 15.0%, p = 0.006) were significantly higher in Yaquis Indians. High blood pressure (6.3 and 3.3%, p = 0.40) and low HDL-cholesterol (42.4 and 34.2%, p = 0.22) were similar between Yaquis and Tepehuanos. Multivariate regression analysis adjusted by sex and age showed a significant association between calorie intake from saturated fat, but not other nutrients of customary diet, with hyperglycemia (OR 7.4, 95% CI 2.6-20.1), hypertriglyceridemia (OR 3.1, 95% CI 1.5-6.3), and obesity (OR 3.4, 95% CI 1.6-10.1). CONCLUSIONS Among the components of acculturation, intake of saturated fat is the most strongly associated with the development of CV risk factors.

Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components.

Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals.

Risk factors for diabetes, but not for cardiovascular disease, are associated with family history of Type 2 diabetes in subjects from central Mexico

Background: Independent of obesity, family history of type 2 diabetes mellitus (FHT2DM) is another important risk factor for developing diabetes. Aim: To establish the association among FHT2DM, risk factors for diabetes and cardiovascular disease in subjects from central Mexico. Subjects and methods: Clinical and biochemical studies were performed in 383 first-degree relatives of patients with type 2 diabetes and 270 subjects unrelated to patients with type 2 diabetes—all subjects were from the city of Puebla in central Mexico. Logistic regressions were used to assess the association between FHT2DM and metabolic parameters. Cardiovascular risk was classified by dyslipidemia and the Framingham Risk Score (FRS). Results: FHT2DM was associated with risk factors for diabetes, such as increased fasting insulin levels (OR = 1.731, 95% CI = 1.041–2.877), decreased insulin sensitivity (OR = 1.951, 95% CI = 1.236–3.080) and pre-diabetes (OR = 1.63, 95% CI = 1.14–2.33). FHT2DH was not associated with risk factors for cardiovascular disease, such as dyslipidemia (OR = 1.12, 95% CI = 0.70–1.79) and FRS (OR = 0.74, 95% CI = 0.40–1.36) when adjusted for gender, age, smoking and obesity. Conclusion: Diabetic risk factors, but not cardiovascular disease risk factors, are associated with a positive family history of diabetes in subjects from central Mexico, independent of the presence of obesity.

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.

Novel insight into streptozotocin-induced diabetic rats from the protein misfolding perspective

Protein folding is a process of self-assembly defined by the sequence of the amino acids of the protein involved. Additionally, proteins tend to unfold, misfold and aggregate due to both intrinsic and extrinsic causes. Human islet amyloid polypeptide (hIAPP) aggregation is an early step in diabetes mellitus. However, the aggregation of rat IAPP (rIAPP) remains an open question. Adult female Sprague-Dawley rats weighing 150–250 g were divided into two groups. The experimental group (streptozotocin [STZ]) (n = 21) received an intraperitoneal injection of a single dose of 40 mg/kg STZ. We used the mouse anti-IAPP antibody and the anti-amyloid oligomer antibody to study the temporal course of rIAPP oligomerization during STZ-induced diabetes using a wide array of methods, strategies and ideas derived from biochemistry, cell biology, and proteomic medicine. Here, we demonstrated the tendency of rIAPP to aggregate and trigger cooperative processes of self-association or hetero-assembly that lead to the formation of amyloid oligomers (trimers and hexamers). Our results are the first to demonstrate the role of rIAPP amyloid oligomers in the development of STZ-induced diabetes in rats. The IAPP amyloid oligomers are biomarkers of the onset and progression of diabetes and could play a role as therapeutic targets.

Prevalence of Prehypertension in Mexico and Its Association With Hypomagnesemia

BACKGROUND Prehypertension (preHTN) increases the risk of developing hypertension. The objectives of this study were to estimate the prevalence of preHTN in the Mexican adult population and evaluate the association between hypomagnesemia and preHTN. METHODS This study was a 2-phase, population-based study. In the first phase, 4,272 Mexican adults (aged 20-65 years) were enrolled to determine the prevalence of preHTN. In the second phase, a cross-sectional analysis was performed to evaluate the association between hypomagnesemia and preHTN. The exclusion criteria were chronic diarrhea, malignancy, hepatic and renal diseases, chronic inflammatory disease, and the intake of magnesium supplements. PreHTN was defined as a systolic blood pressure (BP) of 120-139 mm Hg and/or diastolic BP of 80-89 mm Hg, and hypomagnesemia was defined as a serum magnesium concentration <1.8 mg/dl. RESULTS The prevalence of preHTN was 37.5% (95% confidence interval (CI): 36.0-39.0): 46.7% were men (95% CI: 44.1-49.4) and 33.2% (95% CI: 31.5-5.0) were women. The serum magnesium data were available for 921 participants. Hypomagnesemia was identified in 276 (30.0%; 95% CI: 27.1-33.0) subjects; of them, 176 (63.8%; 95% CI: 58.3-69.6) had preHTN. Individuals with preHTN exhibited lower magnesium levels than individuals without preHTN (1.78±0.36 vs. 1.95±0.37, P < 0.0005). A multiple logistic regression analysis (adjusted for age, sex, smoking, body mass index, waist circumference, fasting glucose, total cholesterol, high-density lipoprotein cholesterol, and triglycerides levels) indicated a significant association between hypomagnesemia and preHTN (odds ratio = 1.78; 95% CI: 1.5-4.0, P < 0.0005). CONCLUSIONS The prevalence of preHTN in the Mexican population is 37.5%, and hypomagnesemia is strongly associated with preHTN.

Clinical testing of propofol geriatic dose for sedation designed via in silico trial

The geriatric population shows significant physiological changes due to aging and the multiple co-morbidities that they often present. Conventionally the propofol sedation dose for patients older than 65 years is 80% of the adult dose. We performed an in silico trial for elderly population and the results showed that the necessary simulated dose of propofol was lower than the conventional dose; therefore, a clinical trial was implemented to test three different propofol doses, two of them lower than the conventional dose, during a pacemaker implantation. The clinical trial showed that there was no clinical difference between the effects of the doses. A BIS monitor was used to measure the level of sedation, which proved to be adequate and well maintained by all patients. All the patients maintained an acceptable level of sedation, measured by a BIS monitor. Since propofol has some dose-dependent secondary effects, the use of lower doses, especially the ones designed for this age group, helps to avoid them.